USE OF ALPHA-1C SPECIFIC COMPOUNDS TO TREAT BENIGN PROSTATIC HYPERPLASIA

Abstract: The subject invention provides a method of treating benign prostatic hyperplasia or inhibiting contraction of a prostate tissue in a subject in need thereof which comprises administering to the subject a therapeutically effective amount of an alpha 1C antagonist which binds to a human alpha 1C adrenergic receptor with a binding affinity greater than 50-fold higher than the binding affinity with which the alpha 1C antagonist binds to a human alpha 1b adrenergic receptor, provided that the alpha 1C antagonist is not 2,6-Dimethyl-4-(4-nitrophenyl)-1, 4-dihydropyridine-3, 5-dicarboxylic acid N-[3-(4,4-diphenylpiperidin-1-yl)-propyl] amide ester hydrochloride hydrate.

Description: USE OF ALPHA-1C SPECIFIC COMPOUNDS TO TREAT BENIGN PROSTATIC HYPERPLASIA This application is a continuation-in-part of U.S. Serial No. 08/228,932, filed April 13, 1994, a continuation-in part of PCT International Application No. PCT/US93/10950, filed November 12, 1993, and U.S. Serial No. 07/975,867, filed November 13, 1992, the contents of which are hereby incorporated by reference. Background of the Invention Benign Prostatic Hyperplasia (BPH) , also called Benign Prostatic Hypertrophy, is a progressive condition which is characterized by a nodular enlargement of prostatic tissue resulting in obstruction of the urethra. This results in increased frequency of urination, nocturia, a poor urine stream and hesitancy or delay in starting the urine flow. Chronic consequences of BPH can include hypertrophy of bladder smooth muscle, a decompensated bladder and an increased incidence of urinary tract infection. The specific biochemical, histological and pharmacological properties of the prostate adenoma leading to the bladder outlet obstruction are not yet known. However, the development of BPH is considered to be an inescapable phenomenon for the aging male population. BPH is observed in approximately 70% of males over the age of 70. Currently, in the United States, the method of choice for treating BPH is surgery (Lepor, H., Urol. Clinics North Amer., 17, 651 (1990)) . Over 400,000 prostatectomies are performed annually (data from 1986) . A medicinal alternative to surgery is clearly very desirable. The limitations of surgery for treating BPH include the morbidity rate of an operative procedure in elderly men, persistence or recurrence of obstructive and irritative symptoms, as well as the significant cost of surgery. θ!-Adrenergic receptors are specific neuroreceptor proteins located in the peripheral and central nervous systems on tissues throughout the body. These receptors are important switches for controlling many physiological functions and, thus, represent important targets for drug development. In fact, many αt-adrenergic drugs have been developed over the past 40 years. Examples include clonidine, phenoxybenzamine and prazosin (treatment of hypertension) , naphazoline (nasal decongestant) , and apraclonidine (treating glaucoma) . αj-Adrenergic drugs can be broken down into two distinct classes: agonists (clonidine and naphazoline are agonists) , which mimic the receptor activation properties of the endogenous neurotransmitter norepinephrine, and antagonists (phenoxybenzamine and prazosin are antagonists) , which act to block the effects of norepinephrine. Many of these drugs are effective but also produce unwanted side effects (for example, clonidine produces dry mouth and sedation in addition to its antihypertensive effects) . During the past 15 years a more precise understanding of ot-adrenergic receptors and their drugs has evolved through increased scientific scrutiny. Prior to 1977, only one α;-adrenergic receptor was known to exist. Between 1977 and 1988, it was accepted by the scientific community that at least two α;-adrenergic receptors--of ! and o! 2 --existed in the central and peripheral nervous systems. Since 1988, new techniques in molecular biology have led to the identification of at least six a-adrenergic receptors which exist throughout the central and peripheral nervous systems: o; 1A , o; 1B , a ιc , o; 2A , α 2B and a 2C (Bylund, D.B., FASEB J. , 6, 832 (1992)) . It is not known precisely which physiological responses in the body are controlled by each of these receptors. In addition, many of-adrenergic drugs that were developed before 1992 are not selective for any particular α!-adrenergic receptor. Many of these drugs produce untoward side effects which may be attributed to their poor o;-adrenergic receptor selectivity. Since the mid 1970's, nonselective a-antagonists have been prescribed to treat BPH. In 1976, M. Caine, et al. (Brit. J. Urol., 48, 255 (1976)), reported that the nonselective o;-antagonist phenoxybenzamine was useful in relieving the symptoms of BPH. This drug may produce its effects by interacting with α-receptors located on the prostate. However, this drug also produces significant side effects which severely limit its use in treating patients on a chronic basis. More recently, the Q!-adrenergic antagonists prazosin and terazosin have also been found to be useful for treating BPH. However, these drugs also produce untoward side effects. The most recently approved drug Proscar" (Merck) prescribed for BPH is not an α-adrenergic antagonist, but rather acts by blocking 5-Q!-reductase. While Proscar is able to relieve symptoms, it is effective in only 30% of all patients, and requires a period of up to 6 months to show results. From binding studies using cloned rat α 1A , hamster a 1B , and bovine o; lc receptors, and functional studies of antagonism ■ in vitro using human prostrate, I. Marshall, et al. , con- eluded that the receptor mediating contraction of the human prostrate is of the c ιc subtype (Marshall, I., et al., Brit. Pharmacol. Soc, (1992)) . Furthermore, using cloned human receptors the binding characteristics of the known BPH drugs to various receptor subtypes have been determined, as described more fully hereinafter. Based upon such binding information and additional data, it has been observed that the side effects which occur with the drugs prazosin and terazosin may be due to their poor selectivity for specific α-adrenergic receptors. In contrast, indoramin is a drug which is slightly selective for the human oι lc receptor relative to the other human o;-adrenergic receptors, but it also interacts at human histamine HI receptors. This compound produces untoward side effects which may be attributed to its activity at such E receptors. It would be desirable to provide methods and compounds which allow the treatment of BPH but which avoid the production of side effects observed for all currently used medications. From the binding information described hereinafter, it has unexpectedly been discovered that compounds which are specific for an α ιc adrenergic receptor with a binding affinity greater than ten-fold higher than the binding affinity with which the compounds bind to an α 1A adrenergic receptor, a human α 1B adrenergic receptor, and a human histamine H x receptor, and (b) bind to an a 2 adrenergic receptor with a binding affinity which is greater than ten-fold lower than the binding affinity with which the compounds bind to such <x lc adrenergic receptor are effective for the treatment of BPH. Furthermore, we have characterized several antagonists selective for the α: lc adrenergic receptor using a rat orthostatic hypotension model to ascertain the vascular effects of drugs which may be indicative of their ability to produce dizziness in patients, and observed that while nonselective alpha 1 antagonists produce significant effects on orthostatic hypotension, selective alpha lc antagonists do not produce significant effects. Summary of the Invention The subject invention provides a method of treating benign prostatic hyperplasia or inhibiting contraction of a prostate tissue in a subject in need thereof which comprises administering to the subject a therapeutically effective amount of an o; lc antagonist which binds to a human α lc adrenergic receptor with a binding affinity greater than 50-fold higher than the binding affinity with which the α lc antagonist binds to a human c lb adrenergic receptor, provided that the αf lc antagonist is not 2,6-Dimethyl-4- (4-nitrophenyl) -1, 4-dihydropyridine- 3, 5-dicarboxylic acid N- [3- (4, 4-diphenylpiperdin-l-yl) - propyl] amide ester hydrochloride hydrate. Brief Description of the Figures Figure 1 Figure 1 illustrates compounds which are potent antagonists of the cloned human α ιc receptor. Figure 2 Panel A illustrates the correlation of inhibition constants (pK ± ) for a series of α^ antagonists at the cloned human o; 1A receptors with efficiency of blocking contraction of human prostate tissue (pA 2 ) . Panel B illustrates the correlation of inhibition constants (pK x ) for a series of antagonists at the cloned human α 1B receptors with efficiency of blocking contraction of human prostate tissue (pA 2 ) . Panel C illustrates the correlation of inhibition constants (pK x ) for a series of a λ antagonists at the cloned human CU 1C receptors with efficiency of blocking contraction of human prostate tissue (pA 2 ) . Detailed Description of the Invention The present invention provides a method of treating benign prostatic hyperplasia or inhibiting contraction of a prostate tissue in a subject in need thereof which comprises administering to the subject a therapeutically effective amount of an ct ιc antagonist which binds to a human o; lc adrenergic receptor with a binding affinity greater than 50-fold higher than the binding affinity with which the o> lc antagonist binds to a human lb adrenergic receptor, provided that the o; lc antagonist is not 2, 6-Dimethyl-4- (4-nitrophenyl) -1, 4-dihydropyridine- 3, 5-dicarboxylic acid N- [3- (4, 4-diphenylpiperdin-l-yl) - propyl] amide ester hydrochloride hydrate. In a preferred embodiment, the α ιc antagonist used to practice the method of the invention additionally binds to a human α la adrenergic receptor, a human ot 2 adrenergic receptor and a human histamine H x receptor with a binding affinity which is greater than ten-fold lower than the binding affinity with which the c lc antagonist binds to the α lc adrenergic receptor. Desirably, the α lc antagonist used to practice the method of the invention additional binds to the human a lc adrenergic receptor with a binding affinity greater than 75-fold higher than the binding affinity with which the 0! 1C antagonist binds to the human α lb adrenergic receptor. Alternatively or incrementally, the o; lc antagonist used to practice the method of the invention additionally binds to a human α la adrenergic receptor, a human α; 2 adrenergic receptor and a human histamine H- . receptor with a binding affinity which is greater than ten-fold lower than the binding affinity with which the α lc antagonist binds to the a lc adrenergic receptor. Alternatively or incrementally, the or lc antagonist used to practice the method of the invention additionally binds to a calcium channel with a binding affinity which is greater than ten-fold lower than the binding affinity with which the o; lc antagonist binds to the ot lc adrenergic receptor. Alternatively or incrementally, the a lc antagonist used to practice the method of the invention additionally binds to a human dopamine D 2 or human histamine H 2 receptor with a binding affinity which is greater than ten-fold lower than the binding affinity with which the α ιc antagonist binds to the ιc adrenergic receptor. Alternatively or incrementally, the a ιc antagonist used to practice the method of the invention additionally binds to any serotonin receptor with a binding affinity which is greater than ten-fold lower than the binding affinity with which the α; ιc antagonist binds to the α lc adrenergic receptor. Alternatively or incrementally, the a ιc antagonist used to practice the method of the invention additionally binds to a dopamine D 3 , D 4 or D 5 receptor with a binding affinity which is greater than ten-fold lower than the binding affinity with which the α lc antagonist binds to the α lc adrenergic receptor. In one embodiment, the α ιc antagonist used to practice the method of the invention additionally does not cause a fall in blood pressure at dosages effective to alleviate benign prostatic hyperplasia or contraction of the prostate tissue. In a preferred embodiment the α ιc antagonist used to practice the method of the invention additionally does not cause a fall in blood pressure in rats at a dosage of 10 micrograms of lc antagonist per kilogram per rat. A preferred embodiment the invention provides for a method of treating benign prostatic hyperplasia or inhibiting contraction of prostate tissue in a subject in need thereof which comprises administering to the subject a therapeutically effective amount of an α ιc antagonist which binds to a human α lc adrenergic receptor with a binding affinity greater than 100-fold higher than the binding affinity with which the α lc antagonist binds to a human c lb adrenergic receptor and a human histamine H x receptor. Alternatively or incrementally, the α lc antagonist used to practice the method of the invention additionally binds to a human α la adrenergic receptor and a human 2 adrenergic receptor with a binding affinity which is greater than ten-fold lower than the binding affinity with which the Q; 1C antagonist binds to the α lc adrenergic receptor. Desirably, the α ιc antagonist used to practice the method of the invention additional binds to a calcium channel with a binding affinity which is greater than ten-fold lower than the binding affinity with which the α ιc antagonist binds to the α lc adrenergic receptor. Alternatively or incrementally, the α lc antagonist used to practice the method of the invention additionally binds to a human dopamine D 2 or human histamine H 2 receptor with a binding affinity which is greater than ten-fold lower than the binding affinity with which the lc antagonist binds to the c lc adrenergic receptor. Alternatively or incrementally, the α lc antagonist used to practice the method of the invention additionally binds to any serotonin receptor with a binding affinity which is greater than ten-fold lower than the binding affinity with which the a ιc adrenergic receptor. Alternatively or incrementally, the α; ιc antagonist used to practice the method of the invention additionally binds to a dopamine D 3 , D 4 or D 5 receptor with a binding affinity which is greater than ten-fold lower than the binding affinity with which the α ιc antagonist binds to the α ιc adrenergic receptor. In one embodiment, the a lc antagonist used to practice the method of the invention additionally does not cause a fall in blood pressure at dosages effective to alleviate benign prostatic hyperplasia or contraction of the prostate tissue. In a preferred embodiment the α ιc antagonist used to practice the method of the invention additionally does not cause a fall in blood pressure in rats at a dosage of 10 micrograms of a lc antagonist per kilogram per rat. In a preferred embodiment the invention provides for a method of treating benign prostatic hyperplasia in a subject which comprises administering to the subject a therapeutically effective amount of an α ιc antagonist which: a. binds to a human a ιc adrenergic receptor with a binding affinity greater than 100- fold higher than the binding affinity with which the α ιc antagonist binds to a human 0! 1A adrenergic receptor, a human 1B adrenergic receptor, and a human histamine H- L receptor; and b. binds to a human 2 adrenergic receptor with a binding affinity which is greater than 100-fold lower than the binding affinity with which the a lc antagonist binds to such α ιc adrenergic receptor. In a preferred embodiment of the invention provides for a method of inhibiting conoraction of a prostate tissue which comprises contacting the prostate tissue with an effective contraction-inhibiting amount of an α ιc antagonist which: a. binds to a human o; lc adrenergic receptor with a binding affinity greater than 100-fold higher than the binding affinity with which the o; lc antagonist binds to a human α 1A adrenergic receptor, a human α 1B adrenergic receptor, and a human histamine x receptor; and b. binds to a human cn 2 adrenergic receptor with a binding affinity which is greater than 100-fold lower than the binding affinity with which the α lc antagonist binds to such α lc adrenergic receptor. Another embodiment of the inventions provides for a method of inhibiting contraction of a prostate tissue in a subject which comprises administering to the subject an effective contraction-inhibiting amount of an <x ιc antagonist which: a. binds to a human α lc adrenergic receptor with a binding affinity greater than 100-fold higher than the binding affinity with which the c ιc antagonist binds to a human α 1A adrenergic receptor, a human o; 1B adrenergic receptor, and a human histamine H x receptor; and b. binds to a human a 2 adrenergic receptor with a binding affinity which is greater than 100-fold lower than the binding affinity with which the α lc antagonist binds to such α ιc adrenergic receptor. Alternatively or incrementally, the α ιc antagonist used to practice the method of the invention additionally (a) binds to a human a ιc adrenergic receptor with a binding affinity greater than 300-fold higher than the binding affinity with which the α ιc antagonist binds to a human α 1A adrenergic receptor, a human o; 1B adrenergic receptor, and a human histamine K receptor, and (b) binds to a human ot 2 adrenergic receptor with a binding affinity which is greater than 300-fold lower than the binding affinity with which the <x lc antagonist binds to such c ιc adrenergic receptor. Desirably, the α ιc antagonist used to practice the method of the invention additional binds to a calcium channel with a binding affinity which is greater than ten-fold lower than the binding affinity with which the c ιc antagonist binds to the ιc adrenergic receptor. In one embodiment, the α lc antagonist used to practice the method of the invention additionally binds to a calcium channel with a binding affinity which is greater than 20- fold lower than the binding affinity with which the α ιc antagonist binds to the α lc adrenergic receptor. In a more preferred embodiment, the c ιc antagonist used to practice the method of the invention additionally binds to a calcium channel with a binding affinity which is greater than 50-fold lower than the binding affinity with which the < ιc antagonist binds to the α ιc adrenergic receptor. Alternatively or incrementally, the α lc antagonist used to practice the method of the invention additionally binds to a calcium channel with a binding affinity which is greater than 100-fold lower than the binding affinity with which the α ιc antagonist binds to the α ιc adrenergic receptor. Alternatively or incrementally, the ot lc antagonist used to practice the method of the invention additionally binds to a calcium channel with a binding affinity which is greater than 300-fold lower than the binding affinity with which the α lc antagonist binds to the α ιc adrenergic receptor. Alternatively or incrementally, the a ιc antagonist used to practice the method of the invention additionally binds to a human dopamine D 2 or human histamine H 2 receptor with a binding affinity which is greater than ten-fold lower than the binding affinity with which the α ιc antagonist binds to the α lc adrenergic receptor. Alternatively or incrementally, the o; lc antagonist used to practice the method of the invention additionally binds to a human dopamine D 2 or human histamine H 2 receptor with a binding affinity which is greater than 20-fold lower than the binding affinity with which the α ιc antagonist binds to the c ιc adrenergic receptor. Alternatively or incrementally, the α ιc antagonist used to practice the method of the invention additionally binds to a human dopamine D 2 or human histamine H 2 receptor with a binding affinity which is greater than 50-fold lower than the binding affinity with which the α ιc antagonist binds to the α ιc adrenergic receptor. Alternatively or incrementally, the lc antagonist used to practice the method of the invention additionally binds to a human dopamine D 2 or human histamine H 2 receptor with a binding affinity which is greater than 100-fold lower than the binding affinity with which the a ιc antagonist binds to the Qf ιc adrenergic receptor. Alternatively or incrementally, the α ιc antagonist used to practice the method of the invention additionally binds to a human dopamine D 2 or human histamine H 2 receptor with a binding affinity which is greater than 300-fold lower than the binding affinity with which the α ιc antagonist binds to the α ιc adrenergic receptor. Desirably, the α lc antagonist used to practice the method of the invention additionally binds to any serotonin receptor with a binding affinity which is greater than ten-fold lower than the binding affinity with which the at ιc antagonist binds to the a ιc adrenergic receptor. Alternatively or incrementally, the lc antagonist used to practice the method of the invention additionally binds to any serotonin receptor with a binding affinity which is greater than 20-fold lower than the binding affinity with which the a ιc antagonist binds to the a ιc adrenergic receptor. Alternatively or incrementally, the α ιc antagonist used to practice the method of the invention additionally binds to any serotonin receptor with a binding affinity which is greater than 50-fold lower than the binding affinity with which the α ιc antagonist binds to the α ιc adrenergic receptor. Alternatively or incrementally, the a ιc antagonist used to practice the method of the invention additionally binds to any serotonin receptor with a binding affinity which is greater than 100-fold lower than the binding affinity with which the α ιc antagonist binds to the α lc adrenergic receptor. Alternatively or incrementally, the α ιc antagonist used to practice the method of the invention additionally binds to any serotonin receptor with a binding affinity which is greater than 300-fold lower than the binding affinity with which the α ιc antagonist binds to the α lc adrenergic receptor. Alternatively or incrementally, the o; lc antagonist used to practice the method of the invention additionally binds to a dopamine D 3 , D 4 , or D 5 receptor with a binding affinity which is greater than ten-fold lower than the binding affinity with which the α ιc antagonist binds to the α ιc adrenergic receptor. Alternatively or incrementally, the α ιc antagonist used to practice the method of the invention additionally binds to a dopamine D 3 , D 4 , or D 5 receptor with a binding affinity which is greater than 20-fold lower than the binding affinity with which the a ιc antagonist binds to the α ιc adrenergic receptor. Alternatively or incrementally, the α ιc antagonist used to practice the method of the invention additionally binds to a dopamine D 3 , D 4 , or D 5 receptor with a binding affinity which is greater than 50-fold lower than the binding affinity with which the o; lc antagonist binds to the α- Lc adrenergic receptor. Alternatively or incrementally, the o; lc antagonist used to practice the method of the invention additionally binds to a dopamine D 3 , D 4 , or D 5 receptor with a binding affinity which is greater than 100-fold lower than the binding affinity with which the α ιc antagonist binds to the c ιc adrenergic receptor. Alternatively or incrementally, the α lc antagonist used to practice the method of the invention additionally binds to a dopamine D 3 , D 4 , or D 5 receptor with a binding affinity which is greater than 300-fold lower than the binding affinity with which the α lc antagonist binds to the Q! 1C adrenergic receptor. Alternatively or incrementally, the o; lc antagonist used to practice the method of the invention additionally does not cause a fall in blood pressure at dosages effective to alleviate benign prostatic hyperplasia. In a preferred embodiment, the α lc antagonist used to practice the method of the invention additionally does not cause a fall in blood pressure in rats at a dosage of 10 micrograms of α ιc antagonist per kilogram per rat. The invention provides for the use of a compound which: a. binds to a human ot lc adrenergic receptor with a binding affinity greater than 100- fold higher than the binding affinity with which the α lc antagonist binds to a human α 1A adrenergic receptor, a human α 1B adrenergic receptor, and a human histamine H- L receptor; and b. binds to a human 2 adrenergic receptor with a binding affinity which is greater than 100-fold lower than the binding affinity with which the α ιc antagonist binds to such α ιc adrenergic receptor in the preparation of a medicament for treating begin prostatic hyperplasia or inhibiting contraction of a ' prostate tissue. In a preferred embodiment of the invention provides for a drug which is useful for treating benign prostatic hyperplasia or inhibiting contraction of a prostate tissue, the effective ingredient of the drug being an < ιc antagonist which: a. binds to a human α ιc adrenergic receptor with a binding affinity greater than 100- fold higher than the binding affinity with which the α lc antagonist binds to a human of 1A adrenergic receptor, a human α 1B adrenergic receptor, and a human histamine H- L receptor; and b. binds to a human 2 adrenergic receptor with a binding affinity which is greater than 100-fold lower than the binding affinity with which the α ιc antagonist binds to such α ιc adrenergic receptor. The present invention provides a method of treating benign prostatic hyperplasia in a subject which comprises administering to the subject a therapeutically effective amount of a compound which (a) binds to a human Q! 1C adrenergic receptor with a binding affinity greater than ten-fold higher than the binding affinity with which the compound binds to a human 1A adrenergic receptor, a human α 1B adrenergic receptor, and a human histamine H x receptor, and (b) binds to a human α 2 adrenergic receptor with a binding affinity which is greater than ten-fold lower than the binding affinity with which the compound binds to such α ιc adrenergic receptor. Ten-fold selectivity differences are a minimum, but one skilled in the art will appreciate that compounds can be found that collectively have almost infinitely variable selectivity profiles. Compounds collectively having all possible combinations of selectivities are intended within the scope of this invention, provided that each of these compounds has at least a ten-fold greater selectivity for the α lc receptor over the α 1A , α 1B , ot 2 and H 2 receptors. For example, compounds useful in the methods of this invention can have at least a 10, 20, 30, 40, 50, 75, 100, 200, 300 or greater fold selectivity for binding to the a ιc receptor over binding to the a 1A , α 1B , a 2 and H 2 receptors. The comopunds useful in the methods of this invention can also have selectivity for the α lc receptor over the α 1A , α 1B , 2 and H 2 receptors, such selectivity having a number-fold between these exemplary integers. Furthermore, these compounds can additionally have selectivity within the ranges described above for binding to the αr lc receptor over binding to (1) a calcium channel; and/or (2) a D 2 or H 2 receptor; and/or (3) any serotonin receptor; and/or (4) a dopamine D 3 , D 4 or D 5 receptor. In the preferred embodiment, the compound (a) binds to a human α ιc adrenergic receptor with a binding affinity greater than 20-, 50-, 100- or 300-fold higher than the binding affinity with which the compound binds to a human α 1A adrenergic receptor, a human 1B adrenergic receptor, and a human histamine E receptor, and (b) binds to a human a 2 adrenergic receptor with a binding affinity which is greater than 20-, 50-, 100- or 300-fold lower than the binding affinity with which the compound binds to such α ιc adrenergic receptor. Desirably, the compound used to practice the method of the invention additionally binds to a calcium channel with a binding affinity which is greater than ten-fold lower than the binding affinity with which the compound binds to the α lc adrenergic receptor. In the preferred embodiment, the compound binds to a calcium channel with a binding affinity which is greater than 20-, 50-, 100- or 300-fold lower than the binding affinity with which the compound binds to the α ιc adrenergic receptor. Alternatively or incrementally, the compound used to practice the method of the invention additionally binds to a human dopamine D 2 receptor or human H 2 receptor with a binding affinity which is greater than ten-fold lower than the binding affinity with which the compound binds to the α ιc adrenergic receptor. In the preferred embodiment, the compound binds to a human dopamine D 2 or human H 2 receptor with a binding affinity which is greater than 20-, 50-, 100- or 300-fold lower than the binding affinity with which the compound binds to the α ιc adrenergic receptor. Alternatively or incrementally, the compound used to practice the method of the invention additionally binds to any serotonin receptor with a binding affinity which is greater than ten-fold lower than the binding affinity with which the compound binds to the < lc adrenergic receptor. In the preferred embodiment, the compound binds to any serotonin receptor with a binding affinity which is greater than 20-, 50-, 100- or 300-fold lower than the binding affinity with which the compound binds to the a ιc adrenergic receptor. Alternatively of incrementally, the compound used to practice the method of the invention also binds to a human dopamine D 3 , D 4 or D 5 receptor with a binding affinity which is greater than ten-fold lower than the binding affinity with which the compound binds to the α ιc adrenergic receptor. In the preferred embodiment, the compound binds to a dopamine D 3 , D 4 , or D 5 receptor with a binding affinity which is greater than 20-, 50-, 100- or 300-fold lower than the binding affinity with which the compound binds to the α ιc adrenergic receptor. Alternatively or incrementally, the compound used to practice the method of the invention also does not cause orthostatic fall in blood pressure at a dosage effective to alleviate benign prostatic hyperplasia or inhibiting contraction of prostate tissue. In one embodiment, the compound used to practice the method of the invention also does not cause orthostatic fall in blood pressure in rats at a dosage 10 ug/kg. A number of compounds have been identified or synthesized which are useful in the practice of the invention. For example, the compound has the structure: In another example, the compound has the structure: In still another example, the compound has the structure In an additional example, the compound has the structure: Included within the scope of the method of treating BPH in accordance with the invention are the use of both R and S enantiomers of the compounds described which possess stereogenic centers, as well as the use of pharmaceutically acceptable salts and complexes thereof. The invention also provides a method of inhibiting contraction of prostate tissue which comprises contacting the prostate tissue with an effective contraction- inhibiting amount of a compound which (a) binds to a human α ιc adrenergic receptor with a binding affinity greater than ten-fold higher than the binding affinity with which the compound binds to a human α 1A adrenergic receptor, a human α 1B adrenergic receptor, and a human histamine H-_ receptor, and (b) binds to a human a 2 adrenergic receptor with a binding affinity which is greater than ten-fold lower than the binding affinity with which the compound binds to such α ιc adrenergic receptor. In the preferred embodiment, the compound (a) binds to a human α ιc adrenergic receptor with a binding affinity greater than 20-, 50-, 100- or 300-fold higher than the binding affinity with which the compound binds to a human 0! IA adrenergic receptor, a human α 1B adrenergic receptor, and a human H x receptor, and (b) binds to a human ot 2 adrenergic receptor with a binding affinity which is greater than 20-, 50-, 100- or 300-fold lower than the binding affinity with which the compound binds to such c ιc adrenergic receptor. The activity of compounds at the different human receptors was determined in vitro using cultured cell lines that selectively express the receptor of interest. These cell lines were prepared by transfecting the cloned cDNA or cloned genomic DNA or constructs containing both genomic DNA and cDNA encoding the human -adrenergic, serotonin, histamine, and dopamine receptors as further described in detail in Example 10 hereinbelow. In connection with this invention, a number of cloned human receptors discussed herein, either as plasmids or as stably transfected cell lines, have been made pursuant to, and in satisfaction of, the Budapest Treaty on the International Recognition of the Deposit of Micro¬ organisms for the Purpose of Patent Procedure, and are made with the American Type Culture Collection, 12301 Parklawn Drive, Rockville, Maryland 20852. Specifically, these deposits have been accorded ATCC Accession Numbers as follows: The data shown in the accompanying Tables indicate that the α ιc -specific receptor antagonists which satisfy the criteria as defined herein have significant efficacy in the inhibition of contraction of human prostate tissue. This in vitro property is recognized in the art as correlating with efficacy in treating benign prostatic hyperplasia in vivo. The present invention therefore provides a method of treating benign prostatic hyperplasia, which comprises administering a quantity of any of the α ιc receptor antagonists defined as herein in a quantity effective against BPH. The drug may be administered to a patient afflicted with benign prostatic hyperplasia by any conventional route of administration, including, but not limited to, intravenous, intramuscular, oral, subcutaneous, intratumoral, intradermal, and parenteral. The quantity effective against BPH is between 0.001 mg and 10.0 mg per kg of subject body weight. The method of treating BPH disclosed in the present invention may also be carried out using a pharmaceutical composition comprising any of the α lc receptor antagonists as defined herein and a pharmaceutically acceptable carrier. The composition may contain between 0.05 mg and 500 mg of an α ιc receptor antagonist, and may be constituted into any form suitable for the mode of administration selected. Compositions suitable for oral administration include solid forms, such as pills, capsules, granules, tablets, and powders, and liquid forms, such as solutions, syrups, elixirs, and suspensions. Forms useful for parenteral administration include sterile solutions, emulsions, and suspensions. The drug may otherwise be prepared as a sterile solid composition which may be dissolved or suspended at the time of administration using sterile water, saline, or other appropriate sterile injectable medium. Carriers are intended to include necessary and inert binders, suspending agents, lubricants, flavorants, sweeteners, preservatives, dyes, and coatings. Optimal dosages to be administered may be readily determined by those skilled in the art, and will vary with the particular α ιc receptor antagonist in use, the strength of the preparation, the mode of administration, and the advancement of the disease condition. Additional factors depending on the particular patient being treated will result in a need to adjust dosages, including patient age, weight, diet, and time of administration. The term "therapeutically effective amount" as used herein means that amount of active agonist or pharmaceutical agent that elicits the biological or medicinal response in a tissue, system, animal or human that is being sought by a researcher, veterinarian, medical doctor or other clinician, which includes alleviation of the symptoms of the disease being treated. The term "subject," as used herein refers to an animal, preferably a mammal, most preferably a human, who has been the object of treatment, observation or experiment. The following Experimental Details are set forth to aid in an understanding of the invention, and are not intended, and should not be construed, to limit in any way the invention set forth in the claims which follow thereafter. Experimental Details Prazosin, 5-methylurapidil, and S-niguldipine were obtained from Research Biochemicals, Inc. A30360 (4- fluoro-4- (8-fluoro-1, 3,4, 5-tetrahydro-2H-pyrido [4,3- b] indol-2-yl)butyrophenone hydrochloride) was obtained from Aldrich Chemical Co. Other compounds were prepared according to the examples which follow. Example 1 Synthesis of Terazosin Hydrochloride N- (2-Furoyl)piperazine This compound and its preparation has been described in Great Britain Patents 1,390,014 and 1,390,015. Piperazine hexahydrate (194 g, 1 mole) was dissolved in 250 ml H 2 0. The solution was acidified to pH 4.5 with 6 N HCl. Furoyl chloride (130.5 g, 1 mole, Aldrich) was added along with 10% NaOH solution at such a rate that the pH was maintained at 4.5. After 1 hour, the solution was made basic (pH = 8.5) with NaOH solution. The reaction mixture was continuously extracted with chloroform for 36 hours. The CHC1 3 extract was dried over MgS0 4 , and filtered. Distillation gave 108.2 g product (60%) , b.p. 132° - 138° C/0.6 mm Hg, m.p. 69° - 70 °C. N- (Tetrahydro-2-furoyl)piperazine The furoylpiperazine of Example 1 was converted to the hydrobromide salt (m.p. 173° - 175° C) . This salt (39.0 g) in 250 ml methyl alcohol and 9.0 g Raney nickel was hydrogenated at 3 atm. After uptake of H 2 ceased, the catalyst was filtered, the solvent concentrated, and the residue crystallized from isopropyl alcohol to give 35.2 g. tetrahydrofuroylpiperazine HBr, m.p. 152° - 156 °C. This was suspended in 20 ml H 2 0. Then 10.5 g 50%, NaOH solution was added slowly followed by 2.0 g solid Na 2 C0 3 . This was extracted with 4 x 100 ml portions of warm CHC1 3 . The CHC1 3 extractions were distilled to give 22.5 g tetrahydrofurolylpiperazine, b.p. 120° - 125°C/0.2 mm Hg. 2 [4- (Tetrahydro-2-furoyl)piperazinyl] -4-amino-6, 7- dimethoxyquinazoline hydrochloride To 7.00 g 2-chloro-4-amino-6,7-dimethoxyquinazoline (Lancaster Synthesis) in 50 ml methoxyethanol was added 10.8 g, tetrahydrofurolylpiperazine, and the mixture refluxed 3 hours. The clear solution was concentrated and an aqueous solution of potassium bicarbonate was added. The resultant solid that formed was filtered and washed with water. It was then added to methanol and the resulting suspension was acidified with a solution of hydrogen chloride in isopropyl alcohol . The resulting solution was concentrated and the residue crystallized from isopropyl alcohol giving 8.12 g. of product, m.p. 278° - 279°C. Example 2 Preparation of Indoramin 4-Benzamido-l- [2- (3-indolyl)ethylpyridinium Bromide A solution of 4-benzamidopyridine (1.98 g) and 3- (2- bromoethyl) indole (2.24 g) in EtOH (15 ml) was refluxed for 2 hours, and the crystallized product (3.13 g, mp 264 266°C) was collected by filtration from the hot reaction mixture. Recyrstallization gave the hydrate. 3- [2-4-Benzamidopiperid-l-yl)ethyl] indole (Indoramin) 4-Benzamido-l- [2- (3-indolyl) ethyl]pyridinium bromide (3.0g) in 91% EtOH (300 ml) containing Et 3 N (0.8 g) was hydrogenated in the presence of freshly prepared W-7 Raney Ni catalyst (ca. 3 g) at 28.12 kg/cm 2 and 50° for 4 hours. After filtering off the catalyst, the filtrate was evaporated and the residue was shaken with CHC1 3 and 2 N NaOH. The resulting insoluble material (1.61 g, mp 203 - 206°C) was collected and dried. Recrystallization from EtOH gave the product (1.34 g) , as colorless needles. Example 3 Preparation of 1- (3-benzoylpropyl) -4-benzamidopiperidine A mixture of 4-chlorobutyrophenone (447 mg, 2.45 mmol), 4-benzamidopiperidine (500 mg, 2.45 mmol) and K 2 C0 3 (338 mg, 2.45 mmol) was heated up in boiling water bath for 1 hour. The reaction mixture was portioned between water and CHC1 3 . The organic layer was separated and dried over Na 2 S0 4 . After filtration and removal of solvent, the residue was purified by chromatography (Si0 2 , MeOH:CHCl 3 , 5:95) . Recrystallization from AcOEt/hexane gave a white powder (78 mg, 8.2%) . mp 143-144°C; -K NMR (CD 3 0D, 400MHz) δ 1.65 (dq, ^=3.16 Hz, J 2 =11.9 Hz, 2H) , 1.90-2.00 (m, 4H) , 2.18 (t, J=11.9 Hz, 2H) , 2.48 (m, 2H) , 3.00-3.10 (m, 4H) , 3.88 (m, IH) , 7.40-8.00 (m, 10H) ; Mass spectrum (M+l) + at m/z 351. Example 4 Preparation of 1- [3- (4-chlorobenzoyl)propyl] -4- benzamidopiperidine A mixture of 3- (4-chlorobenzol)propyl bromide (640 mg, 2.45 mmol), 4-benzamidopiperidine (500 mg, 2.45 mmol) and K 2 C0 3 (1.01 g, 7.34 mmol) in 50 ml of acetone was heated up to refluxing condition for 48 hours. The solid was removed by filtration. Concentration of filtrate in vacuo gave a yellowish solid, which was purified by chromatography (Si0 2 , Me0H:CHCl 3 , 5:95) . 320 mg (33.9%) of white powder was obtained -H NMR (CDC1 3 , 300 mHz) δ 1.46 (dq, J x =1.0 Hz, J 2 =8.4 Hz, 2H) , 1.90-2.10 (m, 4H) , 2.16 (m, 2H) , 2.43 (t, J=6.9 Hz, 2H) , 2.80-2.90 (m, 2H) , 2.97 (t, J=6.9 Hz, 2H) , 3.97 (m, IH) , 5.92 (d, J=7.8 Hz, IH, N-H) , 7.40-8.00 (m, 9H) ; Product was converted to HCl salt and recrystallized with MeOH/Et 2 0, mp 243-244°C; Calcd for C 22 H 25 C1N 2 0 2 ■ HCl ■ H 2 0: C 60.15, H 6.37, N 6.37; Found: C 60.18, H 6.34, N6.29. Exa ple 5 Preparation of SKF-104856 1- [ (4-Chlorophenyl) thio}-2-propanone Chloroacetone (32.3 g, 0.347 mol) was added to a mixture of 4-chlorothiophenol (50 g, 0.347 mmol) and sodium hydroxide (14 g, 0.347 mol) in water (400 ml) and the mixture was stirred at 25°C for 1 hour. The mixture was extracted with ethyl ether and the organic phase was washed with water, dried with magnesium sulfate and concentrated to give 69 g (99%) of l-[(4- chlorophenyl) thio] -2-propanone. 5-Chloro-3-methylbenzo(b) thiophene 1- [ (4-Chlorophenyl) thio} -2-propanone (50 g, 0.25 mol) was added to polyphosphoric acid (300 g) and the mixture was stirred as the temperature was gradually raised to 120°C as an exotherm started. The mixture was stirred at 130°C for 1 hour, diluted with water, extracted with ethyl ether and the organic phase was dried and concentrated. The residue was stirred in methanol (200 ml) , filtered and the filtrate concentrated to give 17.5 g (40%) of 5- chloro-3-methylbenzo(b) thiophene: bp 120°C (0.6 mm Hg) . Ethyl 5-chloro-3-methylbenzo(b) thiophene-2-carboxylate n-Butyllithium in hexane (2.6 M, 2.3 ml) was added to a solution of 5-chloro-3-methylbenzo (b) thiophene (1,0 g, 6 mmol) in ethyl ether (20 ml) stirred at 0°C under argon. The mixture was stirred for 30 minutes and transferred slowly under argon pressure to a stirred solution of ethyl chloroformate (0.63 g, 6 mmol) in ethyl ether (20 ml) . The mixture was stirred at 0°C for 30 minutes and at 25°C for 1.5 hours. The mixture was treated with water and the organic phase was dried, concentrated and triturated with hexane to give 1.0 g (67%) of ethyl 5- chloro-3-methylbenzo (b) thiophene-2-carboxylate: mp 92.5 - 94 °C. Ethyl 3-bromo ethyl-5-chlorobenzo (b) thiophene-2- carboxylate A mixture of ethyl 5-chloro-3-methylbenzo (b) hiophene-2- carboxylate (9.0 g, 0.035 mol), N-bromosuccinimide (6.53 g, 0.037 mol) and benzoyl peroxide (130 mg) in carbon tetrachloride (150 ml) was refluxed and illuminated with sunlamp for 2 hours. The resulting suspension was cooled, filtered and the filter cake was triturated with methanol to give 9.9 g, (85%) of the methanol-insoluble ethyl 3-bromomethyl-5-chlorobenzo (b) thiophene-2- carboxylate: mp 148-150°C. Ethyl 5-Chloro-3- [N- (2,2-dimethoxyethyl) -N-methyl (amino- methyl) ]benzol (b) thiophene-2-carboxylate A mixture of ethyl 3 - bromome t hy1 - 5 - chlorobenzo(b) thiophene-2-carboxylate (11 g, 0.033 mol), methylaminoacetaldehyde dimethyl acetal (4.76 g, 0.04 mol) and potassium carbonate (11.4 g, 0.8 mol) in dry acetone (200 ml) was stirred for 48 hours, filtered and the filtrate concentrated to give 11.8 g, (96%) of ethyl 5 - chloro - 3 - ( N- 2 , 2 - dime thoxye thyl ) - N - methyl (aminomethyl)benzol (b) thiophene-2-carboxylate. Ethyl 7-chloro-3,4-dihydro-4-methylthieno[4 / 3,2-ef] - [3]benzazepine-2-carboxylate Ethyl 5-chloro-3- [N- (2,2-dimethoxyethyl) -N-methyl (amino¬ methyl) ]benzo [b] thiophene-2-carboxylate (3.0 g, 8.1 mmol) was added in portions to trifluoromethanesulfonic acid (10 ml) stirred at 0°C under argon. The mixture was stirred at 25°C for 45 minutes and diluted with water. The mixture was basified with aqueous sodium hydroxide and extracted with ethyl ether to give ethyl 7-chloro- 3,4-dihydro-4-methylthieno- [4,3,2-ef] [3] benzazepine-2- carboxylate. Ethyl 7-chloro-3,4,5,6-tetrahydro-4-methylthieno [4,3,2- ef] [3]benzazepine-2-carboxylate Diborane in tetrahydrofuaran (1 M, 40 ml) was added to a solution of ethyl 7-chloro-3,4-dihydro-4-methylthieno- [4, 3, 2-ef] [3]benzazepine-2-carboxylate (2.8 g) in tetrahydrofuran (30 ml) stirred at 0°C. The mixture was refluxed for 3 hours and stirred at 25°C for 18 hours, cooled, treated with methanol (50 ml) , refluxed for 18 hours and concentrated. The residue was triturated with ethyl ether-hexane (3:1) to give 1.6 g (84%) of ethyl 7- chloro-3 ,4,5, 6-tetrahydro-4-methylthieno [4,3, 2-ef] [3] - benzazepine-2-carboxylate: mp 138-140 °C. The free base was treated with hydrogen chloride to give ethyl 7- chloro-3 ,4,5, 6-tetrahydro-4-methylthieno [4,3,2-ef] - [3] benzazepine-2-carboxylate hydrochloride: mp 240°C. 7-Chloro-3,4,5, 6-tetrahydro-4-methylthieno [4,3,2- ef] [3]benzazepine-2-methanol A solution of ethyl 7-chloro-3,4, 5, 6-tetrahydro-4- methylthieno [ .3.2-ef] [3]benzazepine-2-carboxylate (4.0 g, 12.9 mmol) , in ethyl ether (48 ml) was treated with lithium aluminum hydride (0.53 g, 14 mmol) . The mixture was stirred for 1.5 hours, cooled and treated carefully with water (2.0 ml), 10% sodium hydroxide (1.0 ml) and water (2.0 ml) . The resulting mixture was filtered and the solvent evaporated to give 1.9 g (57%) of 7-chloro- 3 , 4 , 5 , 6 -tetrahydro-4 -methylthieno [4 , 3 , 2 - ef] [3]benzazepine-2-methanol: mp 184-185°C. 7-Chloro-3,4,5, 6-tetrahydro-4-methylthieno-4 ,3,2- ef] [3]benzazepine-2-carboxaldehyde A solution of 7-chloro-3,4, 5, 6-tetrahydro-4-methyl- thieno [4, 3, 2-ef] [3]benzazepine-2-methanol (1.6 g, 6 mmol) in dichloromethane (150 ml) was stirred under argon with activated manganese dioxide (8.3 g) for 2 hours. The mixture was filtered through Celite ™ and the filtrate was dried with magnesium sulfate and concentrated to give a 63% yield of 7-chloro-3 , 4 , 5 , 6-tetrahydro-4- methylthieno [4,3, 2-ef [ [3]benzazepine-2-carboxaldehyde. 7-Chloro-2-ethenyl-3,4,5,6-tetrahdyro-4-methylthieno- [4,3,2-ef] [3]benzazepine (SKF-104856) Sodium hydride (60 % dispersion in mineral oil. 3.8 mmol) was added to a stirred solution of methyltriphenyl- phosphonium bromide (1.35 g, 3.8 mmol) in dry tetra¬ hydrofuran (30 ml) and stirred for 15 minutes. The mixture was treated with a solution of 7-chloro-3,4, 5, 6- tetrahydro-4-methylthieno [4,3, 2-ef] [3] -benzazepine-2- carboxaldehyde, prepared as in Example 3, (0.5 g, 1.9 mmol) in dimethyl-formamide (4 ml) , stirred at 25°C for 16 hours, quenched with ice and extracted with ethyl acetate. The organic phase was washed, dried and concentrated and the residue was chromatographed on silica gel eluted with a gradient of methylene chloride to methanol-methylene chloride (3.5:96.5) . The product was treated with hydrogen chloride to give 0.2 g (35%) of 7-chloro-2-ethenyl-3 ,4,5, 6-tetrahydro-4-methylthieno- [4,3, 2-ef] [3]benzazepine hydrochloride: mp 234-236°C. Example 6 2-Hydroxymethyl-1,2,3,4-tetrahydronaphthalene A solution of 1,2, 34-tetrahydro-2-naphthoic acid (2.50 g, 14.2 mmol) in 100 ml THF was treated with LiAlH 4 (681 mg, 17.04 mmol) and the reaction mixture was heated at reflux for 5 hours. The suspension was cooled to 0°C and quenched by addition of solid Na 2 S0 4 βlOH 2 0. The mixture was stirred at room temperature for 4 hours. The solid was removed by filtration. Concentration of filtrate in vacuo gave a yellowish oil (2.28 g, 98.8%) ; ~ E NMR (CDC1 3 , 300 MHz) δ 1.43 (m, IH) , 2.00 (m, 2H) 2.51 (dd, ^=16.5 Hz, J 2 =10.8 Hz, IH) , 2.85 (m, 3H) , 3.65 (dd, J 1= 6.3 Hz, J 2 =1.2 Hz, 2H) , 7.09 (s, 4H) . 2-Bromomethyl-1,2,3,4-tetrahydronaphthalene A solution of 2-hydroxymethyl-l,2, 3,4-tetrahydronaphtha¬ lene (2.28 g, 14.0 mmol) in 100 ml of CH 2 C1 2 was treated with PBr 3 (1.28 g, 4.73 mmol) at 0°C. The mixture was stirred at room temperature for 72 hours then poured onto 100 g of ice. The organic layer was isolated, washed with 10% K 2 C0 4 aqueous solution, H 2 0, sat'd brine, and then dried over Na 2 S0 4 . After filtration and removal of solvent, the residue was purified by chromatography (Si0 2 , EtOAc:hexane, 1:10) to give a colorless oil (1.33 g, 41.6%) ; -H NMR (CDC1 3 , 300 MHz) δ 1.55 (m, IH) , 2.11 (m, IH) , 2.11 (m, 2H) , 2.58 (dd, J x =16 .2 Hz, J 2 =10.2 Hz, IH) , 2.80-3.10 (m, 3H) , 3.45 (d, J=6.3 Hz, 2H) , 7.10 (m, 4H) . 2- [ (4-Methoxyphenethyl)aminomethyl] -1,2,3,4-tetrahydro- naphthalene (Compound 11) A solution of 2-bromomethyl-l,2,3,4-tetrahydronaphthalene (1.33 g, 5.91 mmol) and 4-methoxyphenethylamine (1.79 g, 11.8 mmol) in 50 ml of EtOH was refluxed for 48 hours. After removal of EtOH .in vacuo, the residue was dissolved in 100 ml of CHC1 3 , washed with 10% 2 C0 3 , H 2 0, sat'd brine, and then dried over Na 2 S0 4 . Filtration followed by evaporation of solvent gave a yellow oil, which was purified by chromatography (Si0 2 , MeOH:CHCl 3 , 5:95) to a give a yellowish oil (1.03 g, 58.9%) . The product was converted to HCl salt, crystallization with MeOH/Et 2 0 gave a white powder, mp 274-275°C; Calcd for C 20 H 25 NO.HCl : C 72.37, H 7.91, N 4.22; Found C 72.40, H 7.76, N 4.13. Exampl« 4,4-Diphenylpiperidine hydrochloride A mixture of 4-piperidone onohydrate hydrochloride (15.0 g, 97.6 mmol, 1.00 equiv, Aldrich) and A1C1 3 (130 g, 976 mmol, 10.0 equiv) in anhydrous benzene (600 mL) was stirred at reflux for 4 hours. Ice (300 g) and water (50 mL) were added, the mixture was filtered, and the solid was washed with toluene and dried to afford 19.2 g (72%) of off-white solid, which was pure by ~ E NMR. Recrystalli- zation from ethanol gave the analytically pure sample: m.p. 300-301 °C; ~ E NMR (300 MHz, CD 3 0D) δ 2.65 (m, 4 H) , 3.18 (m, 4 H) , 7.18 (m, 2 H) , 7.30 (m, 8 H) ; Anal. Calcd. for C 17 H 19 N-HC1: C, 74.57; H. 7.36; N, 5.12. Found: C, 74.32; H, 7.34; N, 5.02. The free base was generated by addition of the above salt to dilute aqueous sodium hydroxide and extraction with CH 2 C1 2 . The organic phase was dried over MgS0 4 and concentrated to give a light brown solid: IR (neat) 2942.8, 1494.5, 1445.9 cm "1 ; CIMS (NH 3 ) m/e 238 (M + 1) + . 3- (4,4-Diphenylpiperidin-1-yl)propionitrile To a suspension of 4,4-diphenylpiperidine hydrochloride (195 mg, 0.712 mmol, 1.0 equiv) in ETOh (1.5 mL) was added triethylamine (0.25 mL, 1.83 mmol, 2.6 equiv) followed by acrylonitrile (0.13 mL, 2.01 mmol, 2.8 equiv) . The resulting solution was stirred at room temperature under argon for 15 minutes and then concentrated. Water was added, and the mixture was extracted three times with EtOAc. The combined organic extracts were dried over MgS0 4 and concentrated to give 170 mg (87%) of tan solid, which was used for the next reaction without purification, m.p. 95-96°C; X H NMR (300 MHz, CDC1 3 ) δ 2.37 (m, 2H) , 2,46 (m, 4H) , 2.52 (m, 6H) , 7.12 (m, 2H) , 7.23 (m, 8H) ; 13 C NMR (75 MHz, CDCl 3 ) δ 16.65, 36.71. 45.08, 50.78, 54.13, 119.70, 126.48, 127.78, 129.11, 147.87; IR (neat) 2944.4, 2821.0, 1495.5, 1445.9 cm -1 . 1- (3-Aminopropyl) -4,4-diphenylpiperidine To a stirred solution of 3- (4,4-diphenylpiperidine-l- yl)propionitrile (2.00 g, 6.89 mmol, 1.0 equiv) in anhydrous THF (20 mL) under argon was added a solution of BH 3 in THF (1.0 M, 24.1 mL, 24 mmol, 3.5 equiv) at room temperature. The mixture was refluxed for 4.5 hours and then cooled to room temperature. Aqueous HCl (6 N, 50 mL) was added and stirring was continued for 1 hour. The mixture was basified to pH 9 by addition of 6 N aq. NaOH, extracted 3 times with CH 2 C1 2 , dried over MgS0 4 and concentrated. The residue was purified by flash chroma- tography (Si0 2 , EtOAc-MeOH, 9:1, followed by EtOAc-MeOH- isopropylamine (60:10:1), followed by EtOAc-MeOH- isopropylamine (40:10:2) to give 1.35 g (66%) of tan solid: m.p. 98-99°C; X H NMR (300 MHz, CDC1 3 ) δ 1.64 (tt, J=7.7 Hz, 2H) , 2.33 (br t, J=7.2 Hz 2H) , 2.50 (m, 8H) , 2.76 (br t, J=6.5 Hz, 2H) , 3.06 (br ε, 2H) , 7.13 (m, 2H) , 7.26 (m, 8H) ; 13 C NMR (75 MHz, CDC1 3 ) δ 29.79, 36.80, 41.41, 45.24, 51.25, 57.41, 126.30, 127.77, 128.97, 148.11; IR (neat) 3361.5 cm "1 ; CIMS (NH 3 ) m/e 295 (M + 1) + . Acetoacetic acid N- [3- (4,4-diphenylpiperidin-l- yl)propyl]amide Diketene (0.44 mL, 5.68 mmol, 1.3 equiv, Aldrich) was added at room temperature to a stirred solution of l-(3- aminopropyl) -4-,4-diphenylpiperidine (1.288 g, 4.37 mmol, 1.0 equiv) in anhydrous toluene (15 mL) under argon, and stirring was continued for 48 hours. The mixture was concentrated to give 1.294 g (78%) of white solid, which was used for the next reaction without purification: X H NMR (300 MHz, CDCl 3 )- δ 1.70 (tt, J=6.4, 6.4 Hz, 2H) , 2.23 (s, 3H) , 2.44 (br t, J=6.5 Hz), 2.49-2.67 (m, 8H) , 3.32 (br t, J=5.8 Hz), 3.36 (s, 2H) , 7.16 (m, 2H) , 7.27 (m, 8H) . 2, 6-Dimethyl-4- (4-nitrophenyl) -1,4-dihydropyridine-3,5- dicarboxylic acid N- [3- (4,4-diphenylpiperidine-1-yl)pro¬ pyl] amide methyl ester A solution of acetoacetic acid N- [3- (4,4-diphenylpiperi- din-l-yl)propyl] amide (365 mg, 0.964 mmol, 1.0 equiv) , methyl 3-aminocrotonate (138 mg, 1.20 mmol, 1.2 equiv, Aldrich), and 4-nitrobenzaldehyde (181 mg, 1.20 mmol, 1.2 equiv, Aldrich) in isopropanol was refluxed under argon for 60 hours. The mixture was cooled to room temperature and concentrated, and the residue was diluted with CH 2 C1 2 , washed with water, dried over MgS0 4 , and concentrated. The residue was purified by flash chromatography (Si0 2 , EtOAc, followed by EtOAc-MeOH, 19:1 and 9:1) to give 147.8 mg (25%) of yellow solid: ~ E NMR (300 MHz, CDC1 3 ) δ 1.55 ( , 2H) , 2.14 (s, 3H) , 2.15-2.50 (m, 10H) , 2.32 (s, 3H) , 3.20 (m, IH) , 3.37 ( , IH) , 3.54 (s, 3H) , 5.00 (s, 3H) , 5.48 (br s) , 6.98 (br t, J=4.9 Hz, IH) , 7.14- 7.30 (m, 10H) , 7.39 (dm, J=8.7 Hz, 2H) , 8.05 (dm, J=8.7 Hz, 2H) ; 13 C NMR (75 MHz, CDCl 3 ) δ 18.74, 20.64, 25.61, 36.77, 40.20, 42.26, 45.03, 51.16, 51.61, 58.08, 100.65, 109.71, 124.35, 126.46, 127.61, 128.84, 129.06, 135.52, 146.96, 147.10, 154.55, 168.22, 168.70; IR (neat) 1680, 1610, 1515, 1340 cm "1 ; MS (FAB) m/e 609 (M + H) + . 2, 6-Dimethyl-4- (4-nitrophenyl) -1,4-dihydropyridine-3,5- dicarboxylic acid N- [3- (4,4-diphenylpiperidin-l-yl) - propyl] amide methyl ester hydrochloride hydrate (Compound 2) To a solution of 2, 6-dimethyl-4- (4-nitrophenyl) -1,4- dihydro-pyridine-3, 5-dicarboxylic acid N-[3-(4,4- diphenylpiperidin-1-yl)propyl] amide methyl ester (147.8 mg, 0.243 mmol, 1.0 equiv) in EtOH (2 mL) was added a solution of HCl in ether (1.0 M, 0.24 mL, 0.24 mmol, 1.0 equiv) . Addition of ethyl acetate (3 mL) followed by heating gave a clear solution. Slow cooling of this solution, followed by filtration gave 91 mg of yellow crystalline solid: m.p. 182-183°C; Anal. Calcd. for C 36 H 40 N 4 O 5 • HCl ■ H 2 0: C, 65.20, H, 6.54; N, 8.45. Found: C, 65.30; H, 6.28; N, 8.15. Example 8 3- (4,4-Diphenylpiperid-l-yl) -propanol 4,4-Diphenylpiperidine (40 g) , 3-bromopropanol (24.7 g, Aldrich) , powdered potassium carbonate (116.4 g) and approximately 1 g of potassium iodide (in 500 ml of a 1:1 mixture of dioxane and 1-butanol) were heated for about 48 hours under reflux and with vigorous stirring. After cooling, the mixture was filtered, and the filtrate was concentrated. The oily residue was taken up in ethyl acetate, and the solution was filtered again. Concen- trating the filtrate to dryness yielded the product in the form of a yellowish, oily residue which slowly solidifies to a wax-like product (yield: 44.8 g) . Hydrochloric acid in ether produced the hydrochloride (m.p.: 226° to 227° C) , which was recrystallized from 2- propanol. Acetoacetic acid 3- (4,4-diphenylpiperidin-1-yl)propyl ester 23.6 g of 3- (4,4-diphenylpiperid-1-yl) -propanol were dissolved in 100 ml of absolute toluene, and 16 ml of a 50% strength solution of diketene in acetone were added with stirring. After standing for several days at room temperature (monitored by thin layer chromatography) , the mixture was concentrated, and the residue was dried under high vacuum. The pale yellow, viscous oil which remains was employed without further purification for the next stage. 2, 6-Dimethyl-4- (4-nitrophenyl) -l,4-dihydropyridine-3,5- dicarboxy-ylic acid [3- (4,4-diphenylpiperidin-l-yl)pro¬ pyl] ester methyl ester A solution of methyl 3-aminocrotonate (265 mg, 2.3 mmol, 1.0 equiv), 4-nitrobenzaldehyde (348 mg, 2.3 mmol, 1.0 equiv) , and acetoacetic acid 3- [4,4-diphenylpiperidin-l- yl)propyl] ester (872 mg, 2.3 mmol, 1.0 equiv) in isopropanol was refluxed under argon with stirring for 68 hours. Cooling and removal of solvent gave a residue, which was purified by flash chromatography (Si0 2 , EtOAc- hexane, 1:1 and 1:2, followed by EtOAc) to afford 717 mg (51%) of yellow solid: X H NMR (300 MHz, CDC1 3 ) δ 1.73 (m, 2H) , 2.22 (m, 2H) , 2.30-2.51 (m, 8H) , 2.34 (s, 3H) , 2.35 (S, 3H) , 3.63 (s, 3H) , 4.05 (dt, J=2.1, 7.9 Hz, 2H) , 5.06 (s, IH) , 5.73 (br s, IH) , 7.14 (m, 2H) , 7.27 (m, 8H) , 7.42 (dm, J=8.8 Hz, 2H) , 8.06 (dm, J=8.8 Hz, 2H) ; 13 C NMR (75 MHz, CDC1 3 ) δ 15.30, 19.65, 26.32, 36.11, 39.88, 44.60, 50.60, 51.12, 55.34, 62.66, 102.99, 107.55, 123.39, 125.67, 127.12, 128.33, 128.65, 144.80, 144.93, 146.36, 147.50, 154.78, 166.91, 167.43; IR (neat) 1698.0, 1684.7, 1517.5, 1345.7 cm "1 ; CIMS (NH 3 ) 610 (M + 1) + , 553, 338. 2, 6-Dimethyl-4- (4-nitrophenyl) -l,4-dihydropyridine-3,5- dicarboxylic acid [3- (4,4-diphenylpiperidin-l-yl)propyl] ester methyl ester hydrochloride (Compound 8) To a solution of 2, 6-dimethyl-4- (4-nitrophenyl) -1,4- dihydro-pyridine-3, 5-dicarboxylic acid [3- (4,4-diphenyl- piperidine-1-yl) -propyl] ester methyl ester (710 mg, 1.16 mmol, 1.0 equiv) in EtOH (5 mL) was added a solution of HCl in ether (1.0 M, 1.5 mL, 1.5 mmol, 1.3 equiv) . The solvents were removed and the residue was dissolved in CH 2 C1 2 . This solution was added dropwise to 25 mL of ether to afford, after filtration, 500 mg of yellow crystalline solid: m.p. 152-153°C. Anal. Calcd. for C 36 H 39 N 3 0 6 • HCl : C, 66.92; H, 6.24; N, 6.50. Found: C, 66.70; H, 5.99; N, 6.27 Example 9 6-Ethyl-4- (4-nitrophenyl) -2- ( (2-aminoethyl) oxy)methyl-5- carboxamido-3- (N- (4,4-diphenylpiperidin-4- yl ) propyl ) carboxamido- 1,4- dihydropyridine (Scheme 1). a. 3- (4,4-Diphenylpiperidin-l-yl)propionitrile. To a suspension of 4,4-diphenylpiperidine hydrochloride (0.195 g, 0.712 mmol) in EtOH (1.5 mL) was added Et 3 N (0.25 mL, 1.8 mmol, 2.6 eq) followed by acrylonitrile (0.13 mL, 2.01 mmol, 2.8 eq) . The resulting solution was stirred at room temperature under argon for 15 min and then concentrated. Water was added, and the mixture was extracted with EtOAc (3 X 10 mL) . The combined organic extracts were dried (MgS0 4 ) and concentrated to give 170 mg (87%) of tan solid, which was characterized spectroscopically and used in the next reaction without purification. b. 3- (4,4-Diphenylpiperidin-l-yl)propylamine. To a stirred solution of 3- (4 , 4-diphenylpiperidin-l-yl) propio- nitrile (2.00 g, 6.89 mmol) in anhydrous THF (20 mL) under argon was added a solution of BH 3 in THF (1.0 M, 24.1 mL, 24 mmol, 3.5 eq) at room temperature. The mixture was refluxed for 4.5 h and then cooled to room temperature. Aqueous HCl (6 N, 50 mL) was added and stirring was continued for 1 h. The mixture was basified to pH 9 by addition of 6 N aq. NaOH, extracted with CH 2 C1 2 (3 X 10 mL) , dried (MgS0 4 ) and concentrated. The residue was purified by flash chromatography (Si0 2 , EtOAc-MeOH- isopropylamine 9:1:0 to 4:1:0.2) to give 1.35 g (66%) of tan solid, which was characterized spectroscopically. c) (±) -6-Ethyl-4- (4-nitrophenyl) -2- (methyloxy)methyl-5- (2- σyanocarboethoxy) - 3 - (carbophenylmethoxy) -1,4- dihydropyridine: A mixture of 3.28 g of ethyl 4-methoxy-3- oxo-butanoate (20.5 mmol) and 4.43 g of benzyl alcohol (41.0 mmol) were heated at 140-150 °C (10-15) for 2 hrs. The reaction mixture was cooled, diluted with 20 mL of ethanol (denatured), 1.90 g of ammonium acetate (24.6 mmol) was added, and the resulting mixture was heated at reflux temperature for 1.5 hrs. The reaction mixture was cooled and 5.27 g of 2-cyanoethyl 2 - (4-nitrobenzilidino) - 3-oxopentanoate was added to the reaction mixture. The resulting mixture was heated at reflux temperature for 2 hrs, cooled, and solvent was removed in vacuo. The crude product was chromatographed on 550 g of silica packed with 10% EtOAc-hexane. The column was eluted with 20% (2 L) , and 30% EtOAc-hexane (4 L) to give 3.08 g (30%) of 6- ethyl-4- (4-nitrophenyl) -2- (methyloxy) methyl-5- (2- cyanocarboethoxy) -3- ( carbophenylmethoxy) -1,4- dihydropyridine as a yellow oil with solidified on standing. The product was used in the next step after spectral characterization. d) (±) -2-Ethyl-4- (4-nitrophenyl) -6- (methyloxy) ethyl-3- (2-cyanocarboethoxy) -1,4-dihydropyridine-3-carboxylic Acid: A suspension of 2.86 g of 6-ethyl-4- (4-nitrophenyl) - 2- (methyloxy) ethyl - 5 - ( 2 - cyanocarboethoxy) -3- (carbophenylmethoxy) -1, -dihydropyridine (5.66 mmol) , 572 mg of 10% Pd/C, 70 mL of methanol, and 2.09 mL of formic acid were stirred at room temperature for 0.5 h. The reaction mixture was diluted with 30 mL of chloroform, filtered through a pad of Celite 545. The filtrate was concentrated in vacuo, and the residue was chromatographed on 250 g of silica packed with 30% EtOAc-hexane. The column was eluted with 50% to 80% EtOAc-hexane (10% change/1 L) to give 1.33 g of 2-ethyl-4- (4-nitrophenyl) -6- (methyloxy) methyl - 3 - ( 2 - cyanocarboethoxy) -1,4- dihydropyridine-3-carboxylic acid (57%) as a yellow oily solid. Anal. Calc. for C 20 H 21 N 3 O 7 : C, 57.83; H, 5.10; N, 10.12. Found: C, 57.78; H, 5.08; N, 9.99. e) (±) -2-Ethyl-4- (4 -nitrophenyl) -6- (methyloxy) methyl-3- (2-cyanocarboethoxy) -5- (N- (4 , 4 -diphenylpiperidin-4 - yl ) propyl ) carboxamido- 1,4 -dihydropyridine, Hemihydrate: A solution of 433 mg of 2-ethyl-4- (4 -nitrophenyl) -6- (methoxy) methyl-3- (2-cyanocarboethoxy) -1, 4- dihydropyridine-3 -carboxylic acid (1.04 mmol), 401 mg of 1- (dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (DMAPECD) (2.09 mmol) , and 153 mg of 4- dimethylaminopyridine (DMAP) (1.25 mmol) in 5 mL of dry dichloromethane were stirred at room temperature for 1 h. The reaction mixture was charged with 328 mg of N- (3- aminopropyl) -4,4-diphenylpiperidine (1.25 mmol) , and the resulting solution was heated at reflux temperature for 2 hrs. The reaction mixture was cooled, and applied to 200 g of silica packed with 5% MeOH-EtOAc. The column was eluted with 10% to 20% MeOH-EtOAc (1 L/5% change) to afford 552 mg of 2-ethyl-4- (4-nitrophenyl) -6- (methyloxy) methyl-3 - (2-cyanocarboethoxy) -5- (N- (4,4- diphenylpiperidin-4 -yl) propyl) carboxamido-1,4- dihydropyridine (77%) as a yellow foamy solid: mp 120-125 °C; Anal. Calc. for C 40 H 45 N 5 O 6 .0.5H 2 0: C, 68.55; H, 6.62; N, 9.99. Found: C, 68.37; H, 6.26; N, 9.98. f ) (±) -2-Ethyl-4- (4 -nitrophenyl) -6- (methyloxy) methyl-5- (N- (4,4- diphenylpiper idin - 4 -y 1 ) propyl ) carboxamido -1,4- dihydropyridine-3-carboxylic Acid: A solution of 40 mg of NaOH in 2 mL of water was added to 530 mg of 2-ethyl-4- (4- nitrophenyl) -6- (methyloxy)methyl-3- (2-cyanocarboethoxy) -5- (N- (4,4-diphenylpiperidin-4-yl)propyl) carboxamido-1,4- dihydropyridine (0.766 mmol) in 10 mL of dioxane. The resulting mixture was stirred at room temperature for 1 h. The solvent was removed in vacuo, the residue was partitioned between 20 mL of water (containing 200 mg of NaOH) and EtOAc (10 mL) , separated, and the organic layer was extracted with 2 X 5 mL of water. The combined aqueous extracts were acidified (concentrated HCl, pH = 3- 4) , and the precipitated oil was extracted with 3 X 10 mL of dichloromethane. The combined organic extracts were dried (Na 2 S0 4 ) , and the solvent was removed in vacuo to afford 472 mg (97%) of 2-ethyl-4- (4-nitrophenyl) -6- (methoxy) ethyl - 5 - (N- (4 , 4 -diphenylpiperidin-4 - yl)propyl) carboxamido-1,4-dihydropyridine-3-carboxylic acid as a yellow solid: mp 120-125 °C (decomp.) ; Anal. Calc. for C 37 H 42 N 4 0 6 .2H 2 0: C, 65.86, H, 6.87; N, 8.30. Found: C, 65.52; H, 7.05; N, 7.89. g. (±) -5-Ethyl-4- (4-nitrophenyl) -2- (methyloxy)methyl-3- (N- (4, 4-diphenylpiperidin-4-yl)propyl) carboxamido-5- carboxamido-1,4-dihydropyridine, Hemihydrate: Amixture of 70.0 mg of 2-ethyl-4- (4-nitrophenyl) -6- (methyloxy)methyl- 5- (N- (4,4-diphenylpiperidin-4-yl)propyl) carboxamido-1,4- dihydropyridine-3-carboxylic acid (0.110 mmol) , 90.5 mg of DCC (0.435 mmol) , and 16.0 mg of DMAP (0.132 mmol) in 5 mL of dry dichloromethane were stirred at room temperature for 1 hr followed by addition of 5 mL of concentrated ammonia. The resulting mixture was heated at reflux temperature for 16 hrs, cooled, filtered, dichloromethane was removed in vacuo, and the residue was dissolved in 5 mL of ethyl acetate (a small amount of dichloromethane was added to make the mixture homogeneous) . The ethyl acetate solution was sequentially washed with aqueous saturated ammonium chloride solution (3 X 2 mL) , aqueous sodium carbonate solution (2 mL) , dried (Na 2 S0 4 ) , and the solvent was removed in vacuo. The residue was chromatographed on 200 g of silica packed with NH 3 (2 M in MeOH) -MeOH-CHCl 3 (1:2:40) . The column was eluted with the same solvent to give 21.0 mg of 5-ethyl-4- (4 -nitrophenyl) -2- (methyloxy) methyl-3 - (N- ( 4 , 4 -diphenylpiperidin-4 - yl) propyl) carboxamido- 5 -carboxamido- 1,4 -dihydropyridine as a yellow solid: mp 89 °C (decomp.) ; Anal. Calc. for C 37 H 43 N 5 0 5 .0.5 H 2 0: C, 68.72; H, 6.86; N, 10.83. Found: C, 68.40; H, 6.91; N, 10.41 h) Ethyl 4- (2,2,2-Trifluoroethyl)oxy-3-oxobutanoate: A solution of 5.00 g of trifluoroethanol (50.0 mol..) in 5 ml of dry THF was added dropwise, over a period of 0.5 hr, to a stirred mixture of 4.00 g of 60% dispersion of NaH (100 mol.), 1.61 g of tetraburylammonium bromide (5.0 mol.), and 830 mg of Nal (5.0 mol.) in 20 ml of dry THF (water bath) . The resulting mixture was stirred for 0.5 hrs, cooled to -30 °C, and a solution of 8.23 g of ethyl 4-chloro-3-oxobutanoate (50.0 mol.) in 10 ml of dry THF was added dropwise, over a period of 15 min, to the reaction mixture. The reaction mixture was warmed to 0 °C over a period of 2 hrs, and stirred at room temperature for 36 hrs. The reaction mixture was quenched with 5 ml of ethanol, partitioned between 100 ml of EtOAc and 100 ml of 10% aqueous HCl solution, separated, extracted with 2 X 40 ml of EtOAc, the combined organic extracts were dried (Na 2 S0 4 ) , and the solvent was removed in vacuo. The crude product was chromatographed on 400 g of silica packed with 5% EtOAc-hexane. The column was eluted with 5 to 25% EtOAc-hexane (1 L/5% change) to afford 8.75 g (77%) of Ethyl 4- (2,2, 2-trifluoroethyl) oxy-3-oxobutanoate as a slightly yellow oil. The product was used in the next step after spectral characterization. i) 2-Cyanoethyl 4- (2,2,2-Trifluoroethyl)oxy-3- oxobutanoate: A mixture of 4.04 g of ethyl 4- (2,2,2- trifluoroethyl) oxy-3-oxobutanoate (17.7 mol.) and 2.55 g of 3-hydroxypropionitrile (35.9 mol.) was heated at reflux temperature at a bath temperature of 135-150 °C at 10 torr for 6 hrs. The reflux condenser was replaced with a distillation head and the product was distilled under reduced pressure to give 4.26 g (96%) of the desired product as a viscous oil: bp 155-158 °C (1.5) . The product was used in the next step after spectral characterization. j) (±) -6-Methyl-4- (4-nitrophenyl) -2- ( (2,2,2- Trif luoroethyl ) oxy) methyl -5-carboxamido-l, 4 - dihydr ' opyridine-3-carboxylic Acid: A mixture of 1.07 g of 2-cyanoethyl 4- (2,2,2-trifluoroethyl) oxy-3-oxobutanoate (4.23 mol.) and 391 mg of ammonium acetate (5.08 mol.) in 5 ml of ethanol were heated at reflux temperature for 15 min, cooled, and 2- (p-nitrobenzilidino) acetoacetamide (4.23 mol.) was added to the reaction mixture. The resulting mixture was heated at reflux temperature for 4.5 hrs, cooled, and a solution of 406 mg of NaOH (10.2 mol.) in 5 ml of water was added to the reaction mixture. The resulting mixture was stirred at room temperature for 0.5 hr. The solvent was removed in vacuo, and the residue was partitioned between EtOAc (20 ml) and water (20 ml containing 300 mg of NaOH) , separated, and the organic layer was extracted with 2 X 10 ml of water (each containing 150 mg of NaOH) . The combined aqueous extracts were filtered, acidified to pH 2-3 with concentrated HCl, and the separated oil was extracted with 50 and then 2 X 20 ml of EtOAc. The combined EtOAc extracts were dried (MgS0 4 ) , and the solvent was removed in vacuo. The crude product crystallized upon trituration with ethyl acetate to give 450 mg of 6-methyl-4- (4-nitrophenyl) -2- ( (2,2, 2- trifluoroethyl) oxy)methyl-5-carboxamido-l, 4 - dihydropyridine-3-carboxylic acid (26%) as a yellow crystalline solid: mp 184 °C (decomp.) ; Anal. Calc. for C 17 H 16 N 3 F 3 0 6 : C, 49.16; H, 3.88; N, 10.12. Found: 48.81; H, 3.97; N, 9.80. k) (±) -6-Methyl-4- (4-nitrophenyl) -2- ( (2,2,2- trifluoroethyl) oxy)methyl-5-carboxamido-3-N- ( (4,4- diphenylpiperidin- 4 -yl) propyl) carboxamido- 1,4- dihydropyridine: A mixture of 102 mg of 6-methyl-4- (4- nitrophenyl) -2- ( (2,2, 2-trifluoroethyl) oxy) methyl-5- carboxamido-1,4-dihydropyridine-3-carboxylic acid (0.230 mol.), 72.0 mg of N-3-aminopropyl-4,4-diphenylpiperidine (0.276 mol.), 119 mg of DCC (0.575 mol.), and 31.0 mg of DMAP (0.253 mol.) in 5 ml of dry dichloromethane were heated at reflux temperature for 3 hrs, cooled, filtered, and the solvent was removed in vacuo. The residue was dissolved in 5 ml of EtOAc, and sequentially washed with saturated aqueous ammonium chloride solution (2 X 2 ml) , saturated aqueous sodium carbonate solution (2 ml) , dried (Na 2 S0 4 ) , and directly applied to 200 g of silica packed with 2N NH 3 (in methanol) -MeOH-CHC1 3 (1:2:20) . The column was eluted with the same solvent system to afford 140 mg of product as a yellow solid (87%) : mp 89 °C (decomp.) ; Anal. Calc. for C 37 H 40 N s F 3 O 5 : C, 64.24; H, 5.83; N, 10.12. Found: C, 63.90; H, 5.87; N, 9.66 1) (±) -6-Ethyl-4- (4-nitrophenyl) -2- ( (2- azidoethyl) oxy)methyl-5- (2-cyanocarboethoxy) -3- (1, 1- dimethyl)carboethoxy-1,4-dihydropyridine: A mixture of 1.00 g of t-butyl 4- (2-azidoethoxy) -3-oxopentanoate (4.10 mol.) and concentrated ammonia (0.800 g, 24.6 mol.) in 1.5 ml of t-BuOH was stirred at room temperature 17 hrs. The solvent was remove in vacuo to a give a yellow viscous oil which was used in the next step after spectral characterization. A mixture of the resulting enamide, and 0.850 g of 2-cyanoethyl 2-benzilidino-3-oxopentanoate in 15 ml of t-BuOH was heated at reflux temperature for 5 hrs. The reaction mixture was concentrated in vacuo, and the crude product was chromatographed on silica (EtOAc- hexane, 1:3) to give 836 mg of 6-ethyl-4- (4-nitrophenyl) - 2- ( (2-azidoethyl)oxy)methyl-5- (2-cyanocarboethoxy) -3- (1,1- dimethyl) carboethoxy-1,4-dihydropyridine (56%) as ayellow viscous oil: Anal. Calc. for C 25 H 30 N 6 O 7 : C, 57.02; H, 5.25; N, 15.95. Found: C, 56.77; H, 5.67; N, 15.69. m) (±) -6-Ethyl-4- (4-nitrophenyl) -2- ( (2- azidoethyl)oxy) ethyl-3- (1, 1-dimethyl) carboethoxy-1,4- dihydropyridine-5-carboxylic Acid: A solution of 91 mg of sodium hydroxide (2.3 mol.) in 7.5 ml of water was added to a solution of 800 mg of 6-ethyl-4- (4-nitrophenyl) -2- ( (2-azidoethyl) oxy)methyl-5- (2-cyanocarboethoxy) -3- (1,1- dimethyl) carboethoxy-1,4-dihydropyridine (1.52 mol.) in 7.5 ml of dioxane. The resulting mixture was stirred at room temperature for 3.5 hrs. The reaction mixture was washed with ether (10 ml) , and the ether extract was back- washed with water (basic at pH = 9-10) . The combined aqueous extracts were acidified (pH = 4) , and the precipitated solid was collected to give the desired acid as a yellow solid (600 mg, 83%) : mp 170-173 °C; Anal. Calc. for C 22 H 27 N 5 0 7 : C, 55.80; H, 5.76; N, 14.78. Found: C, 56.07; H, 5.76; N, 14.73. n) (±) -6-Ethyl-4- (4-nitrophenyl) -2- ( (2- azidoethyl) oxy)methyl-5- (N- (4,4-diphenylpiperidin-4- yDpropyl) carboxamido-3- (1, 1-dimethyl) carboethoxy-1,4- dihydropyridine: A mixture of 300 mg of 6-ethyl-4- (4- nitrophenyl) -2 - ( (2 -azidoethyl) oxy) methyl-3 - (1,1- dimethyl) carboethoxy-l,4-dihydropyridine-5-carboxylic acid (0.634 mol.) , 182 mg of DMAPECD, and 93 mg of DMAP in 8 ml of dry dichloromethane were stirred at room temperature for 3 hrs. The reaction mixture was charged with 216 mg of N- (3-aminopropyl) -4,4-diphenylpiperidine (0.824 mol.) , and heated at reflux temperature for 19 hrs. The reaction mixture was concentrated in vacuo and the crude product was chromatographed (5% MeOH-EtOAc) to give 400 mg of desired product (86%) as a yellow foamy solid: mp 62-67 °C; Anal. Calc. for C 42 H 51 N 7 0 6 : C, 67.26; H, 6.89; N, 13.07. Found: C, 66.96; H, 6.79; N, 12.87. o) (±)-6-Ethyl-4-(4-nitrophenyl) -2-((2- aminoethyl) oxy) ethyl- 5- (N- (4, 4-diphenylpiperidin-4- yl) propyl) carboxamido- 3- (1, 1- dimethyl) carboe thoxy- 1, 4- dihydropyridine : A solution of 136 mg of 6-ethyl-4- (4- nitrophenyl) -2- ( (2 -azidoethyl) oxy) methyl- 5- (N- (4,4- diphenylpiperidin-4-yl) propyl) carboxamido -3 - (1,1- dimethyl) carboe thoxy- 1,4 -dihydropyridine (0.180 mol.), 57 mg of triphenylphosphine (0.22 mol.) , and 5 ml of water in 3.5 ml of ethyl acetate were stirred at room temperature for 13 hrs. The reaction mixture was concentrated in vacuo and the crude product was chromatographed on silica (2N NH 3 (in methanol) -MeOH- CHC1 3 , 1:1:9) to give 25 mg of ethyl-4- (4 -nitrophenyl) -2- ( (2-aminoethyl) oxy)methyl-5- (N- (4, 4 -diphenylpiper idin- 4 -yl) propyl) carboxamido- 3- (1,1- dimethyl) carboethoxy- 1, 4 -dihydropyridine as a light yellow foamy solid: mp 84-89 °C; Anal. Calc. for C 42 H 53 N 5 0 6 .0.7H 2 0 : C, 68.49; H, 7.44; N, 9.51. Found: C, 68.14; H, 7.00; N, 9.41. p) (±) -2 -Ethyl-4 - ( 4 - ni t r opheny 1 ) -6- ( (2 - azidoethyl) oxy) methyl-3 - (2 -cyanocarboethoxy) -1,4- dihydropyridine-5-carboxylic Acid: A mixture of 2.90 g of 6-ethyl-4- (4 -nitrophenyl) -2- ( (2 -azidoethyl) oxy) tnethyl-5 - (2 -cyanocarboethoxy) -3- (1 , 1-dimethyl) carboethoxy-1 , 4- dihydropyridine (5.51 mol.) in 10 ml of formic acid was stirred for 1.5 hrs, solvent removed in vacuo. The crude product was triturated with EtOAc and a small amount of hexane and the resulting precipitated yellow product was collected (700 mg) : mp 150 °C (decomp.) . The product was used in the following steps after spectral characterization . q) (±)-2-Ethyl-4-(4-nitr opheny l)-6- ((2- azidoethyl) oxy)methyl-5- (N- (4, 4 - diphenylpiper idin- 4- yl) propyl) carboxamido- 3 - (2 -cyanocarboethoxy) -1,4- dihydropyridine : A solution of 700 mg of ethyl-4- (4- nitrophenyl) -6- ( ( 2 - az idoethyl ) oxy ) methyl - 3 - (2- cyanocarboethoxy) -1, 4-dihydropyridine-5-carboxylic acid (1.49 mol.) , 461 mg of DCC (2.23 mol.), and 145 mg of DMAP (1.19 mol.) in 10 ml of dry dichloromethane were stirred at room temperature for 1.5 hrs. The reaction mixture was charged with 570 mg of N- (3-aminopropyl) -4,4- diphenylpiperidine (1.93 mol.) , and the reaction mixture was stirred for 13 hrs. The reaction mixture was filtered and applied to a flash chromatography column (silica, MeOH-EtOAc 5% to 10%) to give 815 mg of the desired product (73%) as a yellow foamy solid: mp 63-67 °C; Anal. Calc. for C 41 H 46 N 8 0 6 .H 2 0: C, 64.38; H, 6.33; N, 14.65. Found: C, 64.72; H, 6.12; N, 14.62. r) (±) -2 -Ethyl-4- (4 - i tropheny1 ) -6- ( (2 - azidoethyl) oxy)methyl-5- (N- (4,4-diphenylpiperidin-4- yl) ropyl) carboxamido-1,4-dihydropyridine-3-carboxylic Acid: A solution of sodium hydroxide (30 mg) in 2 ml of water was added to a solution of 356 mg of 2-ethyl-4- (4- nitrophenyl) -6- ( (2-azidoethyl) oxy) methyl-5- (N- (4,4- diphenylpiperidin-4 -yl ) propyl ) carboxamido-3 - (2 - cyanocarboethoxy) -1,4-dihydropyridine (0.500 mol. ) in 2 ml of dioxane. The resulting mixture was stirred at room temperature for 2 hrs. The solvent was removed in vacuo. The residue was dissolved in 10 ml of water and extracted with a 1:1 mixture of ether-hexane (10 ml) . The aqueous extract was acidified to pH 4 (concentrated HCl) , and the precipitated yellow solid was collected to give 283 mg of 2-ethyl-4- (4-nitrophenyl) -6- ( (2-azidoethyl)oxy)methyl-5- (N- (4, 4-diphenylpiperidin-4-yl)propyl) carboxamido-1,4- dihydropyridine-3-carboxylic acid (82%) : mp 118 °C (decomp.) ; Anal. Calc for C 3β H 43 N 7 0 6 : C, 65.78; H, 6.26; N, 14.12. Found: C, 65.55; H, 6.31; N, 13.96. s) (±) -6-Ethyl-4- ( 4 - ni tr opheny 1 ) -2 - ( (2 - azidoethyl ) oxy) ethyl - 5 - carboxamido- 3 - (N- (4,4- diphenylpiper idin- 4 -yl) ropyl) carboxamido- 1,4- dihydropyridine : A solution of 600 mg of 2-ethyl-4- (4- nitrophenyl) -6- ( (2 -azidoethyl) oxy) methyl-5- (N- (4,4- diphenylpiperidin-4-yl) propyl) carboxamido- 1,4- dihydropyridine-3-carboxylic acid (0.865 mol.), DCC (357 mg, 1.73 mol.), and DMAP (85 mg, 0.692 mol.) in 15 ml of dry dichloromethane was stirred at room temperature for 2 hrs. The reaction mixture was charged with 522 mg of concentrated ammonia solution, and the reaction mixture was stirred at room temperature for 3 days. The reaction mixture was filtered, concentrated in vacuo and the crude product was chromatographed (silica, MeOH-EtOAc, 1:9, 1:8, 1:4) to give 528 mg of product as a yellow foamy solid (88%) : mp 88-93 °C; Anal. Calc. for C 38 H 44 N 8 0 5 .0.5H 2 0: C, 65.03; H, 6.46; N, 15.97. Found: C, 64.80; H, 5.96; N, 15.88. t) (±) -6-Ethyl-4- (4-nitrophenyl) -2- ( (2- amino ethyl ) oxy) methyl - 5 - carboxamido- 3 - (N- (4,4- diphenylpiperidin- 4 -yl) propyl ) carboxamido- 1,4- dihydropyridine : A solution of 61 mg of 6-ethyl-4- (4- nitrophenyl) -2- ( ( 2 -azidoethyl) oxy) ethyl- 5 -carboxamido -3- (N- (4 , 4-diphenylpiperidin-4-yl) propyl) carboxamido- 1 , 4- dihydropyridine (0.088 mol.), triphenylphosphine (30 mg, 0.114 mol.), and water (2.5 mg, 0.141 mol.) in 1 ml EtOAc was stirred at room temperature for 3 days. The reaction mixture was concentrated in vacuo, and chromatographed (silica, NH 3 (2N in methanol) :MeOH:CHCl 3 (1:2:20)) to give 32 mg of 6 -ethyl - 4 - ( 4 -nitrophenyl ) - 2 - ( ( 2 - aminoethyl ) oxy ) me thyl - 5 - carboxamido- 3 - (N- (4,4- diphenylpiperidin- 4 -yl) propyl) carboxamido -1,4- dihydropyridine (55%) as a yellow solid: mp 98-103 °C; Anal. Calc. for C 38 H 46 N 6 0 5 .1.0H 2 O.0.2CH 2 C1 2 : C, 65.38; H, 6.95; N, 11.97. Found: C, 65.39; H, 6.58; N, 11.44. Using trimethylphosphine as the reducing agent, on a large scale (3 mol.), a 93% yield of the 6-ethyl-4- (4- nitrophenyl) -2- ( (2-aminoethyl)oxy)methyl-5-carboxamido-3- (N- (4, 4-diphenylpiperidin-4-yl)propyl) carboxamido-1, 4- dihydropyridine was realized. The product from this batch had the following microanalytical data: Anal. Calc. for C 38 H 46 N 6 0 5 .1.3 H 2 0: C, 66.12; H, 7.10; N, 12.18. Found: C, 66.17; H, 6.69; N, 12.09 u) The enantiomers of 6-ethyl-4- (4 -nitrophenyl) -2- ( (2- ami no ethyl ) oxy) methyl-5-carboxamido-3- (N- (4,4- diphenyl peridin- 4 -yl) propyl) carboxamido-1,4- dihydropyridine were separated on a Chiracel AD (2 cm) column. The retention times on the semi -prep column were dependent on the column load. At a 60 mg load, the retention times were 128 and 228 minutes (hexane -ethanol - isopropanol (containing 3% diethylamine) 84:3:13) . The retention times on the analytical Chiracel AD column (4.6 mm) , using the same solvent mixture were 34 and 54 minutes (broad peaks) . The plus isomer eluted first followed by the minus isomer. The purity of the final selected enantiomeric fractions were >99.9%. (-) -6-Ethyl-4- (4 -nitrophenyl) -2- ( (2-aminoethyl) oxy) methyl - 5-carboxamido-3- (N- (4,4-diphenylpiperidin-4- yl) propyl) carboxamido- 1,4 -dihydropyridine: [a] 100 = -39.8 (+) -6-Ethyl-4- (4 -nitrophenyl) -2- ( (2-aminoethyl) oxy) methyl - 5-carboxamido-3- (N- (4,4-diphenylpiperidin-4- yl ) propyl ) carboxamido- 1 , 4 dihydropyridine : [a] 100 = +40.1 Part I Part II .OH .OH Br N. N.. OH Fart III Scheme 1 Synthetic Scheme for the preparation of 6-Ethyl-4- (4-nitrophenyl)-2-((2-aιιnoethyl)oxy)ιethyl-5-carboιaιido- 3-(N-(4 4-dιphenylpιperιdιn-4-yl)-propyl)carboxamιdo- 1,4-dιhydropyrιdme, Example 9 Scheie 1 (cont ) Synthetic Scheie for the preparation of 6-Ethyl-4- (4-nitrophenyl)-2-((2-at noethyl)oxy)ιethyl-5-carboιaιιdo- 3-CK-(4,4-diphenylpiperidm-4-yl)-propyl)carboxamido- 1.4-dιhydropyrιdme, Exaiiple g Example 10 Protocol for the Determination of the Potency of Antagonists The activity of compounds at the different human receptors was determined in vitro using cultured cell lines that selectively express the receptor of interest. These cell lines were prepared by transfecting the cloned cDNA or cloned genomic DNA or constructs containing both genomic DNA and cDNA encoding the human o;-adrenergic, serotonin, histamine, and dopamine receptors as follows: α 1A Human Adrenergic Receptor: The entire coding region of clA (1719 bp) (Sequence I.D. No. 1), including 150 basepairs of 5' untranslated sequence (5' UT) and 300 bp of 3' untranslated sequence (3' UT) , was cloned into the BamHI and Clal sites of the polylinker-modified eukaryotic expression vector pCEXV-3, called EXJ.HR. The construct involved the ligation of partial overlapping human lymphocyte genomic and hippocampal cDNA clones: 5' sequence were contained on a 1.2 kb Smal-XhoI genomic fragment (the vector-derived BamHI site was used for subcloning instead of the internal insert-derived Smal site) and 3' sequences were contained on an 1.3 kb Xhol- Clal cDNA fragment (the Clal site was from the vector polylinker) . Stable cell lines were obtained by cotrans- fection with the plasmid QJIA/EXJ (expression vector containing the αlA receptor gene) and the plasmid pGCcos3neo (plasmid containing the aminoglycoside transferase gene) into LM(tk " ), CHO, and NIH3T3 cells, using calcium phosphate technique. The cells were grown, in a controlled environment (37°C, 5% C0 2 ) , as monolayers in Dulbecco's modified Eagle's Medium (GIBCO, Grand Island, NY) containing 25mM glucose and supplemented with 10% bovine calf serum, 100 units/ml penicillin g, and 100 μg/ml streptomycin sulfate. Stable clones were then selected for resistance to the antibiotic G-418 (1 mg/ml) , and membranes were harvested and assayed for their ability to bind [ 3 H]prazosin as described below (see "Radioligand Binding assays") . α 1B Human Adrenergic Receptor: The entire coding region of αlB (1563 bp) (Sequence I.D. No. 3), including 200 basepairs and 5' untranslated sequence (5' UT) and 600 bp of 3' untranslated sequence (3' UT) , was cloned into the EcoRI site of pCEXV-3 eukaryotic expression vector. The construct involved ligating the full-length containing EcoRI brainstem cDNA fragment from λ ZapII into the expression vector. Stable cell lines were selected as described above. Human or lc Adrenergic Receptor: The entire coding region of o;lC (1401 bp) (Sequence I.D. No. 5) , including 400 basepairs of 5' untranslated sequence (5' UT) and 200 bp of 3' untranslated sequence (3' UT) , was cloned into the Kpnl site of the polylinker-modified pCEXV-3-derived eukaryotic expression vector, EXJ.RH. The construct involved ligating three partial overlapping fragments: a 5' 0.6kb Hindi genomic clone, a central 1.8 EcoRI hippocampal cDNA clone, and a 3' 0.6Kb PstI genomic clone. The hippocampal cDNA fragment overlaps with the 5' and 3' genomic clones so that the Hindi and PstI sites at the 5' and 3' ends of the cDNA clone, respectively, were utilized for ligation. This full-length clone was cloned into the Kpnl site of the expression vector, using the 5' and 3' Kpnl sites of the fragment, derived from vector (i.e., pBluescript) and 3' -untranslated sequences, respectively. Stable cell lines were selected as described above. Radioligand Binding Assays: Transfected cells from culture flasks were scraped into 5ml of 5mM Tris-HCl, 5mM EDTA, pH 7.5, and lysed by sonication. The cell lysates were centrifuged at 1000 rpm for 5 min at 4°C, and the supernatant was centrifuged at 30,000 x g for 20 min at 4°C. The pellet was suspended in 50mM Tris-HCl, ImM MgCl 2 , and 0.1% ascorbic acid at pH 7.5. Binding of the cϋl antagonist [ 3 H]prazosin (0.5 nM, specific activity 76.2 Ci/mmol) to membrane preparations of LM(tk-) cells was done in a final volume of 0.25 ml and incubated at 37°C for 20 min. Nonspecific binding was determined in the presence of 10 μM phentolamine. The reaction was stopped by filtration through GF/B filters using a cell harvester. Inhibition experiments, routinely consisting of 7 concentrations of the tested compounds, were analyzed using a non-linear regression curve-fitting computer program to obtain Ki values. ce 2 Human Adrenergic Receptors: To determine the potency of Q? ! antagonists at the o; 2 receptors, LM(tk-) cell lines stably transfected with the genes encoding the o; 2A , c 2B , and α 2C receptors were used. The cell line expressing the ot 2A receptor is designated L-α; 2A , and was deposited on November 6, 1992 under ATCC Accession No. CRL 11180. The cell line expressing the α 2B receptor is designated L-NGC- Q! 2B , and was deposited on October 25, 1989 under ATCC Accession No. CRL10275. The cell line expressing the o; 2C receptor is designated L-o; 2C , and was deposited on November 6, 1992 under ATCC Accession No. CRL-11181. Cell lysates were prepared as described above (see Radioligand Binding Assays) , and suspended in 25mM glycylglycine buffer (pH 7.6 at room temperature) . Equilibrium competition binding assay were performed using [3H] rauwolscine (0.5nM) , and nonspecific binding was determined by incubation with lOμM phentolamine. The bound radioligand was separated by filtration through GF/B filters using a cell harvester. Human Histamine H x Receptor: The coding sequence of the human histamine H x receptor, homologous to the bovine H x receptor, was obtained from a human hippocampal cDNA library, and was cloned into the eukaryotic expression vector pCEXV-3. The plasmid DNA for the K x receptor is designated pcEXV-Hl, and was deposited on November 6, 1992 under ATCC Accession No. 75346. This construct was transfected into COS-7 cells by the DEAE-dextran method. Cells were harvested after 72 hours and lysed by sonication in 5mM Tris-HCl, 5mM EDTA, pH 7.5. The cell lysates were centrifuged at 1000 rpm for 5 min at 4°C, and the supernatant was centrifuged at 30,000 x g for 20 min. at 4°C. The pellet was suspended in 37.8 mM NaHP0 4 , 12.2 mM KH 2 P0 4 , pH 7.5. The binding of the histamine H- . antagonist [ 3 H]mepyramine (InM, specific activity: 24.8 Ci/mM) was done in a final volume of 0.25 ml and incubated at room temperature for 60 min. Nonspecific binding was determined in the presence of 10 μM mepyramine. The bound radioligand was separated by filtration through GF/B filters using a cell harvester. Human Histamine H 2 Receptor: The coding sequence of the human H 2 receptor was obtained from a human placenta genomic library, and cloned into the cloning site of PCEXV-3 eukaryotic expression vector. The plasmid DNA for the H 2 receptor is designated pcEXV-H2, and was deposited on November 6, 1992 under ATCC Accession No. 75346. This construct was transfected into C0S-7 cells by the DEAE- dextran method. Cells were harvested after 72 hours and lysed by sonication in 5mM Tris-HCl, 5mM EDTA, pH 7.5. The cell lysates were centrifuged at 1000 rpm for 5 min at 4°C, and the supernatant was centrifuged at 30,000 x g for 20 min at 4 °C. The pellet was suspended in 37.8 mM NaHP0 4 , 12.2 mM K2P0 4 , pH 7.5. The binding of the histamine H 2 antagonist [ 3 H] tiotidine (5nM, specific activity: 70 Ci/mM) was done in a final volume of 0.25 ml and incubated at room temperature for 60 min. Nonspecific binding was determined in the presence of 10 μM histamine. The bound radioligand was separated by filtration through GF/B filters using a cell harvester. Human Serotonin Receptors: 5HT 1Dα , 5HT 1Dβ , 5HT 1E , 5HT 1F Receptors: The cell lysates of LM(tk-) clonal cell line stably transfected with the genes encoding each of these 5HT receptor-subtypes were prepared as described above. The cell line for the 5HT 1Dα receptor, designated as Ltk-8-30-84, was deposited on April 17, 1990, and accorded ATCC Accession No. CRL 10421. The cell for the 5HT 1Dβ receptor, designated as Ltk-11, was deposited on April 17, 1990, and accorded ATCC Accession No. CRL 10422. The cell line for the 5HT 1E receptor, designated 5 HT 1E -7, was deposited on November 6, 1991, and accorded ATCC Accession No. CRL 10913. The cell line for the 5HT 1F receptor, designated L-5-HT 1F , was deposited on December 27, 1991, and accorded ATCC Accession No. ATCC 10957. These preparations were suspended in 50mM Tris-HCl buffer (pH 7.4 at 37°C) containing 10 mM MgCl 2 , 0.2 mM EDTA, lOμM pargyline, and 0.1% ascorbate. The potency of α^ antagonists was determined in competition binding assay by incubation for 30 minutes at 37°C in the presence of 5nM [3H] serotonin. Nonspecific binding was determined in the presence of lOμM serotonin. The bound radioligand was separated by filtration through GF/B filters using a cell harvester. Human 5HT 2 Receptor: The coding sequence of the human 5HT 2 receptor was obtained from a human brain cortex cDNA library, and cloned into the cloning site of pCEXV-3 eukaryotic expression vector. This construct was transfected into COS-7 cells by the DEAE-dextran method. Cells were harvested after 72 hours and lysed by sonication in 5mM Tris-HCl, 5mM EDTA, pH 7.5. This cell line was deposited with the ATCC on October 31, 1989, designated as L-NGC-5HT 2 , and was accorded ATCC Accession No. CRL 10287. The cell lysates were centrifuged at 1000 rpm for 5 minutes at 4°C, and the supernatant was centrifuged at 30,000 x g for 20 minutes at 4°C. The pellet was suspended in 50mM Tris-HCl buffer (pH 7.7 at room temperature) containing 10 mM MgS0 4 , 0.5mM EDTA, and 0.1% ascorbate. The potency of alpha-1 antagonists at 5HT 2 receptors was determined in equilibrium competition binding assays using [3H] ketanserin (InM) . Nonspecific binding was defined by the addition of lOμM mianserin. The bound radioligand was separated by filtration through GF/B filters using a cell harvester. Human Dopamine D 2 Receptors: The potency of α^ anta- gonists at the D2 receptor was determined using membrane preparations from COS-7 cells transfected with the gene encoding the human D 2 receptor. The coding region for the human D2 receptor was obtained from a human striatum cDNA library, and cloned into the cloning site of PCDNA 1 eukariotic expression vector. The plasmid DNA for the D 2 receptor is designated pcEXV-D2, and was deposited on November 6, 1992 under ATCC Accession No. ATC 75344. This construct was transfected into COS-7 cells by the DEAE-dextran method. Cells were harvested after 72 hours and lysed by sonication in 5mM Tris-HCl, 5mM EDTA, pH 7.5. The cell lysates were centrifuged at 1000 rpm for 5 minutes at 4°C, and the supernatant was centrifuged at 30,000 x g for 20 minutes at 4°C. The pellet was suspended in 50 mM Tris-HCl (pH 7.4) containing ImM EDTA, 5mM KCl, 1.5mM CaCl 2 , 4mM MgCl 2 , and 0.1% ascorbic acid. The cell lysates were incubated with [3H] spiperone (2nM) , using lOμM (+)Butaclamol to determine nonspecific binding. Other Dopamine receptors are prepared by known methods (D 3 : Sokoloff, P. et al. , Nature, 347, 146 (1990) , and deposited with the European Molecular Biological Labora¬ tory (EMBL) Genbank as X53944; D 4 : Van Tol, H.H.M. , et al., Nature, 350, 610 (1991), and deposited with EMBL Genbank as X58497; D 5 : Sunahara, R.K., et al. , Nature, 350, 614 (1991), and deposited with EMBL Genbank as X58454-HU HD 5DR) . Determination of the Activity of Antagonists at Calcium Channels The potency of λ antagonists at calcium channels was determined in competition binding assays of [3H] nitren- dipine to membrane fragments of rat cardiac muscle, essentially as described by Glossman and Ferry (Methods in Enzymology 109:513-550, 1985) . Briefly, the tissue was minced and homogenized in 50mM Tris-HCl (pH 7.4) containing O.lmM phenylmethylsulfonyl fluoride. The homogenates were centrifuged at 1000 g for 15 minutes, the resulting supernatant was centrifuged at 45,000 g for 15 minutes. The 45,000 g pellet was suspended in buffer and centrifuged a second time. Aliquots of membrane protein were incubated for 30 minutes at 37°C in the presence of [3H] nitrendipine (InM) , and nonspecific binding was determined in the presence of lOμM nifedipine. The bound radioligand was separated by filtration through GF/B filters using a cell harvester. Example 11 Functional Properties of α x Antagonists in the Human Prostate The efficacy of α^adrenergic antagonists for the treatment of benign prostatic hyperplasia (BPH) is related to their ability to elicit relaxation of prostate smooth muscle. An index of this efficacy can be obtained by determining the potency of a x antagonists to antagonize the contraction of human prostatic tissue induced by an agonist "in vitro". Furthermore, by comparing the potency of subtype selective Q; 1 antagonists in binding assays using human α^ receptors with their potency to inhibit agonist-induced smooth muscle contraction, it is possible to determine which of the a adrenergic receptor subtypes is involved in the contraction of prostate smooth muscle. Methods: Prostatic adenomas were obtained at the time of surgery from patients with symptomatic BPH. These were cut into longitudinal strips of 15mm long and 2-4 mm wide, and suspended in 5ml organ baths containing Krebs buffer (pH 7.4) . The baths were maintained at 37°C and continuously oxygenated with 5% C0 2 and 95% 0 2 . Isometric tension was measured with a Grass Instrument FT03 force transducer interfaced with a computer. Tissue strips were contracted with varying concentrations of phenylephrine after incubating for 20 minutes in the absence and presence of at least three different concentrations of antagonist . Dose-response curves for phenylephrine were constructed, and the antagonist potency (pA 2 ) was estimated by the dose-ratio method. The concentration of some antagonists in the tissue bath was assessed by measuring the displacement of [3H]prazosin by aliquots of the bath medium, using membrane preparations of the cloned human a ιc receptor. This control was necessary to account for losses of antagonist due to adsorption to the tissue bath and/or metabolism during the time the antagonists were equilibrated with the prostate tissue. Results: Table 1 shows that the pA 2 values measured for a series of « ! antagonists in human prostate tissue correlate closely (r=0.76) with the corresponding pK ± values measured in the α lc receptor assays. In contrast, the human prostate pA 2 values correlate poorly with the pKi values measured at the α 1A (r=-0.06) and a 1B (r=-0.24) adrenergic receptors. (See Figure 2 (Panels A-C) . Thus, antagonists which are more potent at blocking the o; lc adrenergic receptor are more effective at blocking the contraction of the human prostate than antagonists which are more potent at the c 1A or a 1B adrenergic receptors. In addition, antagonists which are selective for the α ιc receptor will have a better therapeutic ratio than nonselective α antagonists. With SNAP 5036 (11) , the low pA 2 observed in the prostate may be attributed to tissue absorption or metabolism. Table 2 illustrates the cross reactivity of α^ antagonists at other receptors such as α 2A , α 2B , o; 2C , histamine H 17 H 2 , serotonin 5-HT 1Dα , 5-HT 1D g, 5-HT 1E , 5-HT 1F , 5-HT 2 , and dopamine D 2 . Only compounds SNAP 5036, 5041, and 5089 have binding affinities which are greater than ten-fold higher at α ιc receptors than the binding affinities at other receptors. Tables 3, 4 and 5 show cross reactivity of alpha-1 agonists at cloned human receptors. Table 6 shows a comparison of alpha-1 agonist cross reactivity between human neuronal receptors and human alpha-lC receptor. Table 1. COMPARISON OF THE BINDING POTENCY (pK,) OF ALPHA-1 ANTAGONISTS IN CLONED HUMAN RECEPTORS AND THEIR PROTENCY (pA 2 ) TO INHIBIT PROSTATE SMOOTH MUSCLE CONTRACTION Table 2 CROSS REACTIVITY OF o, ANTAGONISTS AT CLONED HUMAN RECEPTORS (PK,) Table 3 CROSS REACTIVITY OF σ, ANTAGONISTS AT CLONED HUMAN RECEPTORS ND=Not Determined As used herein, SEM means the standard error of the mean Table 3 Continued I i I s . O Table A Continued Alpha adrenergic Ki (nM)' Fold selectivity hAlphaic' n' RECEPTORS SUMMARY Table 6 COMPARISON OP ALPHA-1 ANTAOONIST CROS8REACTIVITT BETWEEN HUMAN NEUROMΛL RECEPTORS AND HUMAN ALPHA-IC RECEPTOR (ANTAOONIST Ri NBURONAL RECEPTOR) (ANTAOONIST KI ALPHA-IC AORENEROIC RECEPTOR) I σ 0 I ND-Not Datamlnad "able 6 Continued Example 11 Functional Properties of α^ Antagonists on Rat Orthostatic Hypertension We have identified a large series of compounds (well over 150 compounds, data not shown) which exemplify the hereinabove described properties of antagonists highly selective for the α ιc adrenergic receptor. That is, these compounds are highly selective Alpha lc anta¬ gonists which have less than 10 fold the affinity at cloned human Alpha la, Alpha lb, Alpha 2a, Alpha 2b, Alpha 2C, Histamine HI, Dopamine D2 and Serotonin receptors. In addition, these compounds have 10 fold lower affinity at calcium channels (data not shown) . We designated five of these highly selective anta¬ gonists for the a lc adrenergic receptor as drugs 21-25 and used them to further characterize highly selective antagonists for the a lc adrenergic receptor. In addition, a number of these selective alpha lc antagonists are potent at inhibiting the phenylephrine stimulated contraction of human prostate as described in Example 11. This is a well established protocol for evaluation the efficacy of drugs which may be useful for the treatment of BPH. In addition, we have examined a number of selective alpha lc antagonists in an in vivo canine prostate model (Felson, D., et al. , J. Urol.. 141, 1230-1233 (1989))which is a well characterized model for evaluating the efficacy of BPH drugs (data not shown) . In this model, selective alpha lc antagnists increase urethral pressure at doses which do not produce sig- nificant decreases in canine blood pressure. In contrast, nonselective alpha 1 antagnists do not have as large a separation between the effects on urethral pressure and the effects on blood pressure. These observations support our premise that a selective alpha lc antagonist will have a better safety profile than a nonselective alpha 1 antagonist. We have further characterized selective alpha lc antagonists in a rat orthostatic hypotension model. This model gives information on the vascular effects of drugs which may be indicative of their ability to produce dizziness in patients (Hieble, J.P., et al. , Cardiovascular Pharmacology. 15, 845 (1990)) . Our objective was to characterize the effects of selective alpha lc antagonists on rat orthostatic hypotension and contrast the results with those obtained using nonselective alpha 1 antagonists. Methods Rat Orthostatic Hypotension Model Adult male Sprague-Dawley normotensive rats were anesthetized with sodium pentobarbital (45mg/kg, i.v.) . The femoral vein and artery of the right hindllimb were cannulated for drug administration and blood pressure monitoring, respectively. Heart rate was determined by a cardiotachometer triggered by the blood pressure pulse. The rats were secured in the supine position to a board that could be tilted 90 degrees. When blood pressure and heart rate had stabilized, the rats were subjected to a 90 degree vertical (head up) tilt for 60 seconds. Changes in blood pressure and heart rate from pre-tilt levels were monitored continuously. The rats were returned to the supine position and blood pressure and heart rate were allowed to stabilize. Either an antagonist selective for the c lc adrenergic receptor (designated drug 21, 22, 23, 24 or 25) , an antagonist nonselective for the o; lc adrenergic receptor (Prazosin or Terazosin) or saline was then administered through venous cannula, either as an i.v. bolus or as an infusion, when blood pressure had stabvilized, the rats were subjected to a second tilt and blood pressure and heart rate wre recorded as described above. Most saline treated rats typically exhibit a greater ability to return their blood pressure toward pre-tilt levels during the second tilt. Data from the second tilt are used in statistical analysis. Results Table 7 shows that while nonselective alpha 1 antagonists produce significant effects on orthostatic hypotension, selective alpha 1 c antagonists do not produce significant effects. More specifically, Prazosin and Terazosin consistently cause orthostasis at the lowest dose (10 ug/kg) and, in some rats, in a dose-dependent manner. Drug 21 causes orthostasis only at the highest dose (1000 ug/kg) in 2 out of 4 rats, while the other antagonists selective for the o; lc adrenergic receptor causes no orthostasis at the highest dose. Placebo and 22, 23, 24, 25 did not induce orthostasis at any dose. Taken all together, this is a positive result since it is believed that orthostatic hypotension contributes to the dizziness ovserved clinically with noselective alpha 1 antagonists. This further supports our premise that a selective alpha lc antagonist will have a better safety profile than a nonselective alpha 1 antagonist. TABLE 7 I ω I + an - mean pos ve or nega ve n ngs, respec ve y +, ♦♦ and +++ are relative to doses of the same drug but not compared to other drugs +/- positive findings found in some rats SEQUENCE LISTING (1) GENERAL INFORMATION: (i) APPLICANTS: Charles Gluchowski, Carlos C. Forray, George Chiu, Theresa A. Branchek, John M. etzel and Paul R. Hartig (ii) TITLE OF INVENTION: USE OF ALPHA-1C SPECIFIC COMPOUNDS TO TREAT BENIGN PROSTATIC HYPERPLASIA (iii) NUMBER OF SEQUENCES: 6 (iv) CORRESPONDENCE ADDRESS: (A) ADDRESSEE: COOPER & DUNHAM (B) STREET: 1185-Avenue of the Americas (C) CITY: New York (D) STATE: New York (E) COUNTRY: U.S.A. (F) ZIP: 10036 (v) COMPUTER READABLE FORM: (A) MEDIUM TYPE: Floppy disk (B) COMPUTER: IBM PC compatible (C) OPERATING SYSTEM: PC-DOS/MS-DOS (D) SOFTWARE: Patentln Release #1.24 (vi) CURRENT APPLICATION DATA: (A) APPLICATION NUMBER: (B) FILING DATE: 4-APR-1995 (C) CLASSIFICATION: (viii) ATTORNEY/AGENT INFORMATION: (A) NAME: White, John P. (B) REGISTRATION NUMBER: 28,678 (C) REFERENCE/DOCKET NUMBER: 41878-D-PCT/JPW/AGL (ix) TELECOMMUNICATION INFORMATION: (A) TELEPHONE: (212) 278-0400 (B) TELEFAX: (212) 391-0525 (C) TELEX: (2) INFORMATION FOR SEQ ID NO:l: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 2140 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS : single (D) TOPOLOGY: unknown (ii) MOLECULE TYPE: DNA (genomic) (iii) HYPOTHETICAL: N (iv) ANTI-SENSE: N (ix) FEATURE: (A) NAME/KEY: CDS (B) LOCATION: 178..1893 (D) OTHER INFORMATION: (xi) SEQUENCE DESCRIPTION: SEQ ID NO:l: CCGGGCCAGG CACGTCCGCT CTCGGACAGC CGCTCCGCGT CACAGGAACT TGGGCAGGAC 60 CCGACGGGAC CCGTGCGCGG AGCTGCATCT GGAGCCCCGC GGCTATGCCC TGTGCTCCCC 120 TCCTGCCGGC CGCTCGTTCT GTGCCCCCGG CCCGGCCACC GACGGCCGCG CGTTGAG 177 ATG ACT TTC CGC GAT CTC CTG AGC GTC AGT TTC GAG GGA CCC CGC CCG 225 Met Thr Phe Arg Asp Leu Leu Ser Val Ser Phe Glu Gly Pro Arg Pro 1 5 10 15 GAC AGC AGC GCA GGG GGC TCC AGC GCG GGC GGC GGC GGG GGC AGC GCG 273 Asp Ser Ser Ala Gly Gly Ser Ser Ala Gly Gly Gly Gly Gly Ser Ala 20 25 30 GGC GGC GCG GCC CCC TCG GAG GGC CCG GCG GTG GGC GGC GTG CCG GGG 321 Gly Gly Ala Ala Pro Ser Glu Gly Pro Ala Val Gly Gly Val Pro Gly 35 40 45 GGC GCG GGC GGC GGC GGC GGC GTG GTG GGC GCA GGC AGC GGC GAG GAC 369 Gly Ala Gly Gly Gly Gly Gly Val Val Gly Ala Gly Ser Gly Glu Asp 50 55 60 AAC CGG AGC TCC GCG GGG GAG CCG GGG AGC GCG GGC GCG GGC GGC GAC 417 Asn Arg Ser Ser Ala Gly Glu Pro Gly Ser Ala Gly Ala Gly Gly Asp 65 70 75 80 GTG AAT GGC ACG GCG GCC GTC GGG GGA CTG GTG GTG AGC GCG CAG GGC 465 Val Asn Gly Thr Ala Ala Val Gly Gly Leu Val Val Ser Ala Gin Gly 85 90 95 GTG GGC GTG GGC GTC TTC CTG GCA GCC TTC ATC CTT ATG GCC GTG GCA 513 Val Gly Val Gly Val Phe Leu Ala Ala Phe lie Leu Met Ala Val Ala 100 105 110 GGT AAC CTG CTT GTC ATC CTC TCA GTG GCC TGC AAC CGC CAC CTG CAG 561 Gly Asn Leu Leu Val lie Leu Ser Val Ala Cys Asn Arg His Leu Gin 115 120 125 ACC GTC ACC AAC TAT TTC ATC GTG AAC CTG GCC GTG GCC GAC CTG CTG 609 Thr Val Thr Asn Tyr Phe lie Val Asn Leu Ala Val Ala Asp Leu Leu 130 135 140 CTG AGC GCC ACC GTA CTG CCC TTC TCG GCC ACC ATG GAG GTT CTG GGC 657 Leu Ser Ala Thr Val Leu Pro Phe Ser Ala Thr Met Glu Val Leu Gly 145 150 155 160 TTC TGG GCC TTT GGC CGC GCC TTC TGC GAC GTA TGG GCC GCC GTG GAC 705 Phe Trp Ala Phe Gly Arg Ala Phe Cys Asp Val Trp Ala Ala Val Asp 165 170 175 GTG CTG TGC TGC ACG GCC TCC ATC CTC AGC CTC TGC ACC ATC TCC GTG 753 Val Leu Cys Cys Thr Ala Ser lie Leu Ser Leu Cys Thr lie Ser Val 180 185 190 GAC CGG TAC GTG GGC GTG CGC CAC TCA CTC AAG TAC CCA GCC ATC ATG 801 Asp Arg Tyr Val Gly Val Arg His Ser Leu Lys Tyr Pro Ala lie Met 195 200 205 ACC GAG CGC AAG GCG GCC GCC ATC CTG GCC CTG CTC TGG GTC GTA GCC 849 Thr Glu Arg Lys Ala Ala Ala lie Leu Ala Leu Leu Trp Val Val Ala 210 215 220 CTG GTG GTG TCC GTA GGG CCC CTG CTG GGC TGG AAG GAG CCC GTG CCC 897 Leu Val Val Ser Val Gly Pro Leu Leu Gly Trp Lys Glu Pro Val Pro 225 230 235 240 CCT GAC GAG CGC TTC TGC GGT ATC ACC GAG GAG GCG GGC TAC GCT GTC 945 Pro Asp Glu Arg Phe Cys Gly lie Thr Glu Glu Ala Gly Tyr Ala Val 245 250 255 TTC TCC TCC GTG TGC TCC TTC TAC CTG CCC ATG GCG GTC ATC GTG GTC 993 Phe Ser Ser Val Cys Ser Phe Tyr Leu Pro Met Ala Val lie Val Val 260 265 270 ATG TAC TGC CGC GTG TAC GTG GTC GCG CGC AGC ACC ACG CGC AGC CTC 1041 Met Tyr Cys Arg Val Tyr Val Val Ala Arg Ser Thr Thr Arg Ser Leu 275 280 285 GAG GCA GGC GTC AAG CGC GAG CGA GGC AAG GCC TCC GAG GTG GTG CTG 1089 Glu Ala Gly Val Lys Arg Glu Arg Gly Lys Ala Ser Glu Val Val Leu 290 295 300 CGC ATC CAC TGT CGC GGC GCG GCC ACG GGC GCC GAC GGG GCG CAC GGC 1137 Arg lie His Cys Arg Gly Ala Ala Thr Gly Ala Asp Gly Ala His Gly 305 310 315 320 ATG CGC AGC GCC AAG GGC CAC ACC TTC CGC AGC TCG CTC TCC GTG CGC 1185 Met Arg Ser Ala Lys Gly His Thr Phe Arg Ser Ser Leu Ser Val Arg 325 330 335 CTG CTC AAG TTC TCC CGT GAG AAG AAA GCG GCC AAG ACT CTG GCC ATC 1233 Leu Leu Lys Phe Ser Arg Glu Lys Lys Ala Ala Lys Thr Leu Ala lie 340 345 350 GTC GTG GGT GTC TTC GTG CTC TGC TGG TTC CCT TTC TTC TTT GTC CTG 1281 Val Val Gly Val Phe Val Leu Cys Trp Phe Pro Phe Phe Phe Val Leu 355 360 365 CCG CTC GGC TCC TTG TTC CCG CAG CTG AAG CCA TCG GAG GGC GTC TTC 1329 Pro Leu Gly Ser Leu Phe Pro Gin Leu Lys Pro Ser Glu Gly Val Phe 370 375 380 AAG GTC ATC TTC TGG CTC GGC TAC TTC AAC AGC TGC GTG AAC CCG CTC 1377 Lys Val lie Phe Trp Leu Gly Tyr Phe Asn Ser Cys Val Asn Pro Leu 385 390 395 400 ATC TAC CCC TGT TCC AGC CGC GAG TTC AAG CGC GCC TTC CTC CGT CTC 1425 lie Tyr Pro Cys Ser Ser Arg Glu Phe Lys Arg Ala Phe Leu Arg Leu 405 410 415 CTG CGC TGC CAG TGC CGT CGT CGC CGG CGC CGC CGC CCT CTC TGG CGT 1473 Leu Arg Cys Gin Cys Arg Arg Arg Arg Arg Arg Arg Pro Leu Trp Arg 420 425 430 GTC TAC GGC CAC CAC TGG CGG GCC TCC ACC AGC GGC CTG CGC CAG GAC 1521 Val Tyr Gly His His Trp Arg Ala Ser Thr Ser Gly Leu Arg Gin Asp 435 440 445 TGC GCC CCG AGT TCG GGC GAC GCG CCC CCC GGA GCG CCG CTG GCC CTC 1569 Cys Ala Pro Ser Ser Gly Asp Ala Pro Pro Gly Ala Pro Leu Ala Leu 450 455 460 ACC GCG CTC CCC GAC CCC GAC CCC GAA CCC CCA GGC ACG CCC GAG ATG 1617 Thr Ala Leu Pro Asp Pro Asp Pro Glu Pro Pro Gly Thr Pro Glu Met 465 470 475 480 CAG GCT CCG GTC GCC AGC CGT CGA AAG CCA CCC AGC GCC TTC CGC GAG 1665 Gin Ala Pro Val Ala Ser Arg Arg Lys Pro Pro Ser Ala Phe Arg Glu 485 490 495 TGG AGG CTG CTG GGG CCG TTC CGG AGA CCC ACG ACC CAG CTG CGC GCC 1713 Trp Arg Leu Leu Gly Pro Phe Arg Arg Pro Thr Thr Gin Leu Arg Ala 500 505 510 AAA GTC TCC AGC CTG TCG CAC AAG ATC CGC GCC GGG GGC GCG CAG CGC 1761 Lys Val Ser Ser Leu Ser His Lys lie Arg Ala Gly Gly Ala Gin Arg 515 520 525 GCA GAG GCA GCG TGC GCC CAG CGC TCA GAG GTG GAG GCT GTG TCC CTA 1809 Ala Glu Ala Ala Cys Ala Gin Arg Ser Glu Val Glu Ala Val Ser Leu 530 535 540 GGC GTC CCA CAC GAG GTG GCC GAG GGC GCC ACC TGC CAG GCC TAC GAA 1857 Gly Val Pro His Glu Val Ala Glu Gly Ala Thr Cys Gin Ala Tyr Glu 545 550 555 560 TTG GCC GAC TAC AGC AAC CTA CGG GAG ACC GAT ATT TAAGGACCCC 1903 Leu Ala Asp Tyr Ser Asn Leu Arg Glu Thr Asp lie 565 570 AGAGCTAGGC CGCGGAGTGT GCTGGGCTTG GGGGTAAGGG GGACCAGAGA GGCGGGCTGG 1963 TGTTCTAAGA GCCCCCGTGC AAATCGGAGA CCCGGAAACT GATCAGGGCA GCTGCTCTGT 2023 GACATCCCTG AGGAACTGGG CAGAGCTTGA GGCTGGAGCC CTTGAAAGGT GAAAAGTAGT 2083 GGGGCCCCCT GCTGGACTCA GGTGCCCAGA ACTCTTTTCT TAGAAGGGAG AGGCTGC 2140 (2) INFORMATION FOR SEQ ID NO:2: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 572 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) MOLECULE TYPE: protein (xi) SEQUENCE DESCRIPTION: SEQ ID NO:2: Met Thr Phe Arg Asp Leu Leu Ser Val Ser Phe Glu Gly Pro Arg Pro 1 5 10 15 Asp Ser Ser Ala Gly Gly Ser Ser Ala Gly Gly Gly Gly Gly Ser Ala 20 25 30 Gly Gly Ala Ala Pro Ser Glu Gly Pro Ala Val Gly Gly Val Pro Gly 35 40 45 Gly Ala Gly Gly Gly Gly Gly Val Val Gly Ala Gly Ser Gly Glu Asp 50 55 60 Asn Arg Ser Ser Ala Gly Glu Pro Gly Ser Ala Gly Ala Gly Gly Asp 65 70 75 80 Val Asn Gly Thr Ala Ala Val Gly Gly Leu Val Val Ser Ala Gin Gly 85 90 95 Val Gly Val Gly Val Phe Leu Ala Ala Phe lie Leu Met Ala Val Ala 100 105 110 Gly Asn Leu Leu Val lie Leu Ser Val Ala Cys Asn Arg His Leu Gin 115 120 125 Thr Val Thr Asn Tyr Phe lie Val Asn Leu Ala Val Ala Asp Leu Leu 130 135 140 Leu Ser Ala Thr Val Leu Pro Phe Ser Ala Thr Met Glu Val Leu Gly 145 150 155 160 Phe Trp Ala Phe Gly Arg Ala Phe Cys Asp Val Trp Ala Ala Val Asp 165 170 175 Val Leu Cys Cys Thr Ala Ser lie Leu Ser Leu Cys Thr lie Ser Val 180 185 190 Asp Arg Tyr Val Gly Val Arg His Ser Leu Lys Tyr Pro Ala lie Met 195 200 205 Thr Glu Arg Lys Ala Ala Ala lie Leu Ala Leu Leu Trp Val Val Ala 210 215 220 Leu Val Val Ser Val Gly Pro Leu Leu Gly Trp Lys Glu Pro Val Pro 225 230 235 240 Pro Asp Glu Arg Phe Cys Gly lie Thr Glu Glu Ala Gly Tyr Ala Val 245 250 255 Phe Ser Ser Val Cys Ser Phe Tyr Leu Pro Met Ala Val lie Val Val 260 265 270 Met Tyr Cys Arg Val Tyr Val Val Ala Arg Ser Thr Thr Arg Ser Leu 275 280 285 Glu Ala Gly Val Lys Arg Glu Arg Gly Lys Ala Ser Glu Val Val Leu 290 295 300 Arg lie His Cys Arg Gly Ala Ala Thr Gly Ala Asp Gly Ala His Gly 305 310 315 320 Met Arg Ser Ala Lys Gly His Thr Phe Arg Ser Ser Leu Ser Val Arg 325 330 335 Leu Leu Lys Phe Ser Arg Glu Lys Lys Ala Ala Lys Thr Leu Ala lie 340 345 350 Val Val Gly Val Phe Val Leu Cys Trp Phe Pro Phe Phe Phe Val Leu 355 360 365 Pro Leu Gly Ser Leu Phe Pro Gin Leu Lys Pro Ser Glu Gly Val Phe 370 375 380 Lys Val lie Phe Trp Leu Gly Tyr Phe Asn Ser Cys Val Asn Pro Leu 385 390 395 400 lie Tyr Pro Cys Ser Ser Arg Glu Phe Lys Arg Ala Phe Leu Arg Leu 405 410 415 Leu Arg Cys Gin Cys Arg Arg Arg Arg Arg Arg Arg Pro Leu Trp Arg 420 425 430 Val Tyr Gly His His Trp Arg Ala Ser Thr Ser Gly Leu Arg Gin Asp 435 440 445 Cys Ala Pro Ser Ser Gly Asp Ala Pro Pro Gly Ala Pro Leu Ala Leu 450 455 460 Thr Ala Leu Pro Asp Pro Asp Pro Glu Pro Pro Gly Thr Pro Glu Met 465 470 475 480 Gin Ala Pro Val Ala Ser Arg Arg Lys Pro Pro Ser Ala Phe Arg Glu 485 490 495 Trp Arg Leu Leu Gly Pro Phe Arg Arg Pro Thr Thr Gin Leu Arg Ala 500 505 510 Lys Val Ser Ser Leu Ser His Lys lie Arg Ala Gly Gly Ala Gin Arg 515 520 525 Ala Glu Ala Ala Cys Ala Gin Arg Ser Glu Val Glu Ala Val Ser Leu 530 535 540 Gly Val Pro His Glu Val Ala Glu Gly Ala Thr Cys Gin Ala Tyr Glu 545 550 555 560 Leu Ala Asp Tyr Ser Asn Leu Arg Glu Thr Asp lie 565 570 (2) INFORMATION FOR SEQ ID NO:3: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 1738 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS : single (D) TOPOLOGY: unknown (ii) MOLECULE TYPE: DNA (genomic) (iii) HYPOTHETICAL: N (iv) ANTI-SENSE: N (ix) FEATURE: (A) NAME/KEY: CDS (B) LOCATION: 124..1683 (D) OTHER INFORMATION: (xi) SEQUENCE DESCRIPTION: SEQ ID NO:3: GCCAGGAGGG CGCCTCTGGG AAGAAGACCA CGGGGGAAGC AAAGTTTCAG GGCAGCTGAG 60 GAGCCTTCGC CGCAGCCCTT CCGAGCCCAA TCATCCCCCA GGCTATGGAG GGCGGACTCT 120 AAG ATG AAT CCC GAC CTG GAC ACC GGC CAC AAC ACA TCA GCA CCT GCC 168 Met Asn Pro Asp Leu Asp Thr Gly His Asn Thr Ser Ala Pro Ala 1 5 10 15 CAC TGG GGA GAG TTG AAA AAT GCC AAC TTC ACT GGC CCC AAC CAG ACC 216 His Trp Gly Glu Leu Lys Asn Ala Asn Phe Thr Gly Pro Asn Gin Thr 20 25 30 TCG AGC AAC TCC ACA CTG CCC CAG CTG GAC ATC ACC AGG GCC ATC TCT 264 Ser Ser Asn Ser Thr Leu Pro Gin Leu Asp lie Thr Arg Ala lie Ser 35 40 45 GTG GGC CTG GTG CTG GGC GCC TTC ATC CTC TTT GCC ATC GTG GGC AAC 312 Val Gly Leu Val Leu Gly Ala Phe lie Leu Phe Ala lie Val Gly Asn 50 55 60 ATC CTA GTC ATC TTG TCT GTG GCC TGC AAC CGG CAC CTG CGG ACG CCC 360 lie Leu Val lie Leu Ser Val Ala Cys Asn Arg His Leu Arg Thr Pro 65 70 75 ACC AAC TAC TTC ATT GTC AAC CTG GCC ATG GCC GAC CTG CTG TTG AGC 408 Thr Asn Tyr Phe lie Val Asn Leu Ala Met Ala Asp Leu Leu Leu Ser 80 85 90 95 TTC ACC GTC CTG CCC TTC TCA GCG GCC CTA GAG GTG CTC GGC TAC TGG 456 Phe Thr Val Leu Pro Phe Ser Ala Ala Leu Glu Val Leu Gly Tyr Trp 100 105 110 GTG CTG GGG CGG ATC TTC TGT GAC ATC TGG GCA GCC GTG GAT GTC CTG 504 Val Leu Gly Arg lie Phe Cys Asp lie Trp Ala Ala Val Asp Val Leu 115 120 125 TGC TGC ACA GCG TCC ATT CTG AGC CTG TGC GCC ATC TCC ATC GAT CGC 552 Cys Cys Thr Ala Ser lie Leu Ser Leu Cys Ala lie Ser lie Asp Arg 130 135 140 TAC ATC GGG GTG CGC TAC TCT CTG CAG TAT CCC ACG CTG GTC ACC CGG 600 Tyr lie Gly Val Arg Tyr Ser Leu Gin Tyr Pro Thr Leu Val Thr Arg 145 150 155 AGG AAG GCC ATC TTG GCG CTG CTC AGT GTC TGG GTC TTG TCC ACC GTC 6 8 Arg Lys Ala lie Leu Ala Leu Leu Ser Val Trp Val Leu Ser Thr Val 160 165 170 175 ATC TCC ATC GGG CCT CTC CTT GGG TGG AAG GAG CCG GCA CCC AAC GAT 696 lie Ser lie Gly Pro Leu Leu Gly Trp Lys Glu Pro Ala Pro Asn Asp 180 185 190 GAC AAG GAG TGC GGG GTC ACC GAA GAA CCC TTC TAT GCC CTC TTC TCC 744 Asp Lys Glu Cys Gly Val Thr Glu Glu Pro Phe Tyr Ala Leu Phe Ser 195 200 205 TCT CTG GGC TCC TTC TAC ATC CCT CTG GCG GTC ATT CTA GTC ATG TAC 792 Ser Leu Gly Ser Phe Tyr lie Pro Leu Ala Val lie Leu Val Met Tyr 210 215 220 TGC CGT GTC TAT ATA GTG GCC AAG AGA ACC ACC AAG AAC CTA GAG GCA 840 Cys Arg Val Tyr lie Val Ala Lys Arg Thr Thr Lys Asn Leu Glu Ala 225 230 235 GGA GTC ATG AAG GAG ATG TCC AAC TCC AAG GAG CTG ACC CTG AGG ATC 888 Gly Val Met Lys Glu Met Ser Asn Ser Lys Glu Leu Thr Leu Arg lie 240 245 250 255 CAT TCC AAG AAC TTT CAC GAG GAC ACC CTT AGC AGT ACC AAG GCC AAG 936 His Ser Lys Asn Phe His Glu Asp Thr Leu Ser Ser Thr Lys Ala Lys 260 265 270 GGC CAC AAC CCC AGG AGT TCC ATA GCT GTC AAA CTT TTT AAG TTC TCC 984 Gly His Asn Pro Arg Ser Ser lie Ala Val Lys Leu Phe Lys Phe Ser 275 280 285 AGG GAA AAG AAA GCA GCT AAG ACG TTG GGC ATT GTG GTC GGT ATG TTC 1032 Arg Glu Lys Lys Ala Ala Lys Thr Leu Gly He Val Val Gly Met Phe 290 295 300 ATC TTG TGC TGG CTA CCC TTC TTC ATC GCT CTA CCG CTT GGC TCC TTG 1080 He Leu Cys Trp Leu Pro Phe Phe He Ala Leu Pro Leu Gly Ser Leu 305 310 315 TTC TCC ACC CTG AAG CCC CCC GAC GCC GTG TTC AAG GTG GTG TTC TGG 1128 Phe Ser Thr Leu Lys Pro Pro Asp Ala Val Phe Lys Val Val Phe Trp 320 325 330 335 CTG GGC TAC TTC AAC AGC TGC CTC AAC CCC ATC ATC TAC CCA TGC TCC 1176 Leu Gly Tyr Phe Asn Ser Cys Leu Asn Pro He He Tyr Pro Cys Ser 340 345 350 AGC AAG GAG TTC AAG CGC GCT TTC GTG CGC ATC CTC GGG TGC CAG TGC 1224 Ser Lys Glu Phe Lys Arg Ala Phe Val Arg He Leu Gly Cys Gin Cys 355 360 365 CGC GGC CGC GGC CGC CGC CGA CGC CGC CGC CGC CGT CGC CTG GGC GGC 1272 Arg Gly Arg Gly Arg Arg Arg Arg Arg Arg Arg Arg Arg Leu Gly Gly 370 375 380 TGC GCC TAC ACC TAC CGG CCG TGG ACG CGC GGC GGC TCG CTG GAG CGC 1320 Cys Ala Tyr Thr Tyr Arg Pro Trp Thr Arg Gly Gly Ser Leu Glu Arg 385 390 395 TCG CAG TCG CGC AAG GAC TCG CTG GAC GAC AGC GGC AGC TGC CTG AGC 1368 Ser Gin Ser Arg Lys Asp Ser Leu Asp Asp Ser Gly Ser Cys Leu Ser 400 405 410 415 GGC AGC CAG CGG ACC CTG CCC TCG GCC TCG CCG AGC CCG GGC TAC CTG 1416 Gly Ser Gin Arg Thr Leu Pro Ser Ala Ser Pro Ser Pro Gly Tyr Leu 420 425 430 GGC CGC GGC GCG CCA CCG CCA GTC GAG CTG TGC GCC TTC CCC GAG TGG 1464 Gly Arg Gly Ala Pro Pro Pro Val Glu Leu Cys Ala Phe Pro Glu Trp 435 440 445 AAG GCG CCC GGC GCC CTC CTG AGC CTG CCC GCG CCT GAG CCC CCC GGC 1512 Lys Ala Pro Gly Ala Leu Leu Ser Leu Pro Ala Pro Glu Pro Pro Gly 450 455 460 CGC CGC GGC CGC CAC GAC TCG GGC CCG CTC TTC ACC TTC AAG CTC CTG 1560 Arg Arg Gly Arg His Asp Ser Gly Pro Leu Phe Thr Phe Lys Leu Leu 465 470 475 ACC GAG CCC GAG AGC CCC GGG ACC GAC GGC GGC GCC AGC AAC GGA GGC 1608 Thr Glu Pro Glu Ser Pro Gly Thr Asp Gly Gly Ala Ser Asn Gly Gly 480 485 490 495 TGC GAG GCC GCG GCC GAC GTG GCC AAC GGG CAG CCG GGC TTC AAA AGC 1656 Cys Glu Ala Ala Ala Asp Val Ala Asn Gly Gin Pro Gly Phe Lys Ser 500 505 510 AAC ATG CCC CTG GCG CCC GGG CAG TTT TAGGGCCCCC GTGCGCAGCT 1703 Asn Met Pro Leu Ala Pro Gly Gin Phe 515 520 TTCTTTCCCT GGGGAGGAAA ACATCGTGGG GGGGA 1738 (2) INFORMATION FOR SEQ ID NO:4: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 520 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) MOLECULE TYPE: protein (xi) SEQUENCE DESCRIPTION: SEQ ID NO:4: Met Asn Pro Asp Leu Asp Thr Gly His Asn Thr Ser Ala Pro Ala His 1 5 10 15 Trp Gly Glu Leu Lys Asn Ala Asn Phe Thr Gly Pro Asn Gin Thr Ser 20 25 30 Ser Asn Ser Thr Leu Pro Gin Leu Asp He Thr Arg Ala .He Ser Val 35 40 45 Gly Leu Val Leu Gly Ala Phe He Leu Phe Ala He Val Gly Asn He 50 55 60 Leu Val He Leu Ser Val Ala Cys Asn Arg His Leu Arg Thr Pro Thr 65 70 75 80 Asn Tyr Phe He Val Asn Leu Ala Met Ala Asp Leu Leu Leu Ser Phe 85 90 95 Thr Val Leu Pro Phe Ser Ala Ala Leu Glu Val Leu Gly Tyr Trp Val 100 105 110 Leu Gly Arg He Phe Cys Asp He Trp Ala Ala Val Asp Val Leu Cys 115 120 125 Cys Thr Ala Ser He Leu Ser Leu Cys Ala He Ser He Asp Arg Tyr 130 135 140 He Gly Val Arg Tyr Ser Leu Gin Tyr Pro Thr Leu Val Thr Arg Arg 145 150 155 160 Lys Ala He Leu Ala Leu Leu Ser Val Trp Val Leu Ser Thr Val He 165 170 175 Ser He Gly Pro Leu Leu Gly Trp Lys Glu Pro Ala Pro Asn Asp Asp 180 185 190 Lys Glu Cys Gly Val Thr Glu Glu Pro Phe Tyr Ala Leu Phe Ser Ser 195 200 205 Leu Gly Ser Phe Tyr He Pro Leu Ala Val He Leu Val Met Tyr Cys 210 215 220 Arg Val Tyr He Val Ala Lys Arg Thr Thr Lys Asn Leu Glu Ala Gly 225 230 235 240 Val Met Lys Glu Met Ser Asn Ser Lys Glu Leu Thr Leu Arg He His 245 250 255 Ser Lys Asn Phe His Glu Asp Thr Leu Ser Ser Thr Lys Ala Lys Gly 260 265 270 His Asn Pro Arg Ser Ser He Ala Val Lys Leu Phe Lys Phe Ser Arg 275 280 285 Glu Lys Lys Ala Ala Lys Thr Leu Gly He Val Val Gly Met Phe He 290 295 300 Leu Cys Trp Leu Pro Phe Phe He Ala Leu Pro Leu Gly Ser Leu Phe 305 310 315 320 Ser Thr Leu Lys Pro Pro Asp Ala Val Phe Lys Val Val Phe Trp Leu 325 330 335 Gly Tyr Phe Asn Ser Cys Leu Asn Pro He He Tyr Pro Cys Ser Ser 340 345 350 Lys Glu Phe Lys Arg Ala Phe Val Arg He Leu Gly Cys Gin Cys Arg 355 360 365 Gly Arg Gly Arg Arg Arg Arg Arg Arg Arg Arg Arg Leu Gly Gly Cys 370 375 380 Ala Tyr Thr Tyr Arg Pro Trp Thr Arg Gly Gly Ser Leu Glu Arg Ser 385 390 395 400 Gin Ser Arg Lys Asp Ser Leu Asp Asp Ser Gly Ser Cys Leu Ser Gly 405 410 415 Ser Gin Arg Thr Leu Pro Ser Ala Ser Pro Ser Pro Gly Tyr Leu Gly 420 425 430 Arg Gly Ala Pro Pro Pro Val Glu Leu Cys Ala Phe Pro Glu Trp Lys 435 440 445 Ala Pro Gly Ala Leu Leu Ser Leu Pro Ala Pro Glu Pro Pro Gly Arg • 450 455 460 Arg Gly Arg His Asp Ser Gly Pro Leu Phe Thr Phe Lys Leu Leu Thr 465 470 475 480 Glu Pro Glu Ser Pro Gly Thr Asp Gly Gly Ala Ser Asn Gly Gly Cys 485 490 495 Glu Ala Ala Ala Asp Val Ala Asn Gly Gin Pro Gly Phe Lys Ser Asn 500 505 510 Met Pro Leu Ala Pro Gly Gin Phe 515 520 (2) INFORMATION FOR SEQ ID NO:5: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 1639 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS : single (D) TOPOLOGY: unknown (ii) MOLECULE TYPE: DNA (genomic) (iii) HYPOTHETICAL: N (iv) ANTI-SENSE: N (ix) FEATURE: (A) NAME/KEY: CDS (B) LOCATION: 126..1523 (D) OTHER INFORMATION: (xi) SEQUENCE DESCRIPTION: SEQ ID NO:5: CCAGCCAAAC CACTGGCAGG CTCCCTCCAG CCGAGACCTT TTATTCCCGG CTCCCGAGCT 60 CCGCCTCCGC GCCAGCCCGG GAGGTGGCCC TGACAGCCGG ACCTCGCCCG GCCCCGGCTG 120 GGACC ATG GTG TTT CTC TCG GGA AAT GCT TCC GAC AGC TCC AAC TGC 167 Met Val Phe Leu Ser Gly Asn Ala Ser Asp Ser Ser Asn Cys 1 5 10 ACC CAA CCG CCG GCA CCG GTG AAC ATT TCC AAG GCC ATT CTG CTC GGG 215 Thr Gin Pro Pro Ala Pro Val Asn He Ser Lys Ala He Leu Leu Gly 15 20 25 30 GTG ATC TTG GGG GGC CTC ATT CTT TTC GGG GTG CTG GGT AAC ATC CTA 263 Val He Leu Gly Gly Leu He Leu Phe Gly Val Leu Gly Asn He Leu 35 40 45 GTG ATC CTC TCC GTA GCC TGT CAC CGA CAC CTG CAC TCA GTC ACG CAC 311 Val He Leu Ser Val Ala Cys His Arg His Leu His Ser Val Thr His 50 55 60 TAC TAC ATC GTC AAC CTG GCG GTG GCC GAC CTC CTG CTC ACC TCC ACG 359 Tyr Tyr He Val Asn Leu Ala Val Ala Asp Leu Leu Leu Thr Ser Thr 65 70 75 GTG CTG CCC TTC TCC GCC ATC TTC GAG GTC CTA GGC TAC TGG GCC TTC 407 Val Leu Pro Phe Ser Ala He Phe Glu Val Leu Gly Tyr Trp Ala Phe 80 85 90 GGC AGG GTC TTC TGC AAC ATC TGG GCG GCA GTG GAT GTG CTG TGC TGC 455 Gly Arg Val Phe Cys Asn He Trp Ala Ala Val Asp Val Leu Cys Cys 95 100 105 110 ACC GCG TCC ATC ATG GGC CTC TGC ATC ATC TCC ATC GAC CGC TAC ATC 503 Thr Ala Ser He Met Gly Leu Cys He He Ser He Asp Arg Tyr He 115 120 125 GGC GTG AGC TAC CCG CTG CGC TAC CCA ACC ATC GTC ACC CAG AGG AGG 551 Gly Val Ser Tyr Pro Leu Arg Tyr Pro Thr He Val Thr Gin Arg Arg 130 135 140 GGT CTC ATG GCT CTG CTC TGC GTC TGG GCA CTC TCC CTG GTC ATA TCC 599 Gly Leu Met Ala Leu Leu Cys Val Trp Ala Leu Ser Leu Val He Ser 145 150 155 ATT GGA CCC CTG TTC GGC TGG AGG CAG CCG GCC CCC GAG GAC GAG ACC 647 He Gly Pro Leu Phe Gly Trp Arg Gin Pro Ala Pro Glu Asp Glu Thr 160 165 170 ATC TGC CAG ATC AAC GAG GAG CCG GGC TAC GTG CTC TTC TCA GCG CTG 695 He Cys Gin He Asn Glu Glu Pro Gly Tyr Val Leu Phe Ser Ala Leu 175 180 185 190 GGC TCC TTC TAC CTG CCT CTG GCC ATC ATC CTG GTC ATG TAC TGC CGC 743 Gly Ser Phe Tyr Leu Pro Leu Ala He He Leu Val Met Tyr Cys Arg 195 200 205 GTC TAC GTG GTG GCC AAG AGG GAG AGC CGG GGC CTC AAG TCT GGC CTC 791 Val Tyr Val Val Ala Lys Arg Glu Ser Arg Gly Leu Lys Ser Gly Leu 210 215 220 AAG ACC GAC AAG TCG GAC TCG GAG CAA GTG ACG CTC CGC ATC CAT CGG 839 Lys Thr Asp Lys Ser Asp Ser Glu Gin Val Thr Leu Arg He His Arg 225 230 235 AAA AAC GCC CCG GCA GGA GGC AGC GGG ATG GCC AGC GCC AAG ACC AAG 887 Lys Asn Ala Pro Ala Gly Gly Ser Gly Met Ala Ser Ala Lys Thr Lys 240 245 250 ACG CAC TTC TCA GTG AGG CTC CTC AAG TTC TCC CGG GAG AAG AAA GCG 935 Thr His Phe Ser Val Arg Leu Leu Lys Phe Ser Arg Glu Lys Lys Ala 255 260 265 270 GCC AAA ACG CTG GGC ATC GTG GTC GGC TGC TTC GTC CTC TGC TGG CTG 983 Ala Lys Thr Leu Gly He Val Val Gly Cys Phe Val Leu Cys Trp Leu 275 280 285 CCT TTT TTC TTA GTC ATG CCC ATT GGG TCT TTC TTC CCT GAT TTC AAG 1031 Pro Phe Phe Leu Val Met Pro He Gly Ser Phe Phe Pro Asp Phe Lys 290 295 300 CCC TCT GAA ACA GTT TTT AAA ATA GTA TTT TGG CTC GGA TAT CTA AAC 1079 Pro Ser Glu Thr Val Phe Lys He Val Phe Trp Leu Gly Tyr Leu Asn 305 310 315 AGC TGC ATC AAC CCC ATC ATA TAC CCA TGC TCC AGC CAA GAG TTC AAA 1127 Ser Cys He Asn Pro He He Tyr Pro Cys Ser Ser Gin Glu Phe Lys 320 325 330 AAG GCC TTT CAG AAT GTC TTG AGA ATC CAG TGT CTC TGC AGA AAG CAG 1175 Lys Ala Phe Gin Asn Val Leu Arg He Gin Cys Leu Cys Arg Lys Gin 335 340 345 350 TCT TCC AAA CAT GCC CTG GGC TAC ACC CTG CAC CCG CCC AGC CAG GCC 1223 Ser Ser Lys His Ala Leu Gly Tyr Thr Leu His Pro Pro Ser Gin Ala 355 360 365 GTG GAA GGG CAA CAC AAG GAC ATG GTG CGC ATC CCC GTG GGA TCA AGA 1271 Val Glu Gly Gin His Lys Asp Met Val Arg He Pro Val Gly Ser Arg 370 375 380 GAG ACC TTC TAC AGG ATC TCC AAG ACG GAT GGC GTT TGT GAA TGG AAA 1319 Glu Thr Phe Tyr Arg He Ser Lys Thr Asp Gly Val Cys Glu Trp Lys 385 390 395 TTT TTC TCT TCC ATG CCC CGT GGA TCT GCC AGG ATT ACA GTG TCC AAA 1367 Phe Phe Ser Ser Met Pro Arg Gly Ser Ala Arg He Thr Val Ser Lys 400 405 410 GAC CAA TCC TCC TGT ACC ACA GCC CGG GTG AGA AGT AAA AGC TTT TTG 1415 Asp Gin Ser Ser Cys Thr Thr Ala Arg Val Arg Ser Lys Ser Phe Leu 415 420 425 430 CAG GTC TGC TGC TGT GTA GGG CCC TCA ACC CCC AGC CTT GAC AAG AAC 1463 Gin Val Cys Cys Cys Val Gly Pro Ser Thr Pro Ser Leu Asp Lys Asn 435 440 445 CAT CAA GTT CCA ACC ATT AAG GTC CAC ACC ATC TCC CTC AGT GAG AAC 1511 His Gin Val Pro Thr He Lys Val His Thr He Ser Leu Ser Glu Asn 450 455 460 GGG GAG GAA GTC TAGGACAGGA AAGATGCAGA GGAAAGGGGA ATATCTTAGG 1563 Gly Glu Glu Val 465 TACCATACCC TGGAGTTCTA GAGGATTCCT CGACAAGCTT ATTCCGATCC AGACATGATA 1623 GATACATTGA TGAGTT 1639 (2) INFORMATION FOR SEQ ID NO:6: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 466 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) MOLECULE TYPE: protein (xi) SEQUENCE DESCRIPTION: SEQ ID NO:6: Met Val Phe Leu Ser Gly Asn Ala Ser Asp Ser Ser Asn Cys Thr Gin 1 5 10 15 Pro Pro Ala Pro Val Asn He Ser Lys Ala He Leu Leu Gly Val He 20 25 30 Leu Gly Gly Leu He Leu Phe Gly Val Leu Gly Asn He Leu Val He 35 40 45 Leu Ser Val Ala Cys His Arg His Leu His Ser Val Thr His Tyr Tyr 50 55 60 He Val Asn Leu Ala Val Ala Asp Leu Leu Leu Thr Ser Thr Val Leu 65 70 75 80 Pro Phe Ser Ala He Phe Glu Val Leu Gly Tyr Trp Ala Phe Gly Arg 85 90 95 Val Phe Cys Asn He Trp Ala Ala Val Asp Val Leu Cys Cys Thr Ala 100 105 110 Ser He Met Gly Leu Cys He He Ser He Asp Arg Tyr He Gly Val 115 120 125 Ser Tyr Pro Leu Arg Tyr Pro Thr He Val Thr Gin Arg Arg Gly Leu 130 135 140 Met Ala Leu Leu Cys Val Trp Ala Leu Ser Leu Val He Ser He Gly 145 150 155 160 Pro Leu Phe Gly Trp Arg Gin Pro Ala Pro Glu Asp Glu Thr He Cys 165 170 175 Gln He Asn Glu Glu Pro Gly Tyr Val Leu Phe Ser Ala Leu Gly Ser 180 185 190 Phe Tyr Leu Pro Leu Ala He He Leu Val Met Tyr Cys Arg Val Tyr 195 200 205 Val Val Ala Lys Arg Glu Ser Arg Gly Leu Lys Ser Gly Leu Lys Thr 210 215 220 Asp Lys Ser Asp Ser Glu Gin Val Thr Leu Arg He His Arg Lys Asn 225 230 235 240 Ala Pro Ala Gly Gly Ser Gly Met Ala Ser Ala Lys Thr Lys Thr His 245 250 255 Phe Ser Val Arg Leu Leu Lys Phe Ser Arg Glu Lys Lys Ala Ala Lys 260 265 270 Thr Leu Gly He Val Val Gly Cys Phe Val Leu Cys Trp Leu Pro Phe 275 280 285 Phe Leu Val Met Pro He Gly Ser Phe Phe Pro Asp Phe Lys Pro Ser 290 295 300 Glu Thr Val Phe Lys He Val Phe Trp Leu Gly Tyr Leu Asn Ser Cys 305 310 315 320 He Asn Pro He He Tyr Pro Cys Ser Ser Gin Glu Phe Lys Lys Ala 325 330 335 Phe Gin Asn Val Leu Arg He Gin Cys Leu Cys Arg Lys Gin Ser Ser 340 345 350 Lys His Ala Leu Gly Tyr Thr Leu His Pro Pro Ser Gin Ala Val Glu 355 360 365 Gly Gin His Lys Asp Met Val Arg He Pro Val Gly Ser Arg Glu Thr 370 375 380 Phe Tyr Arg He Ser Lys Thr Asp Gly Val Cys Glu Trp Lys Phe Phe 385 390 395 400 Ser Ser Met Pro Arg Gly Ser Ala Arg He Thr Val Ser Lys Asp Gin 405 410 415 Ser Ser Cys Thr Thr Ala Arg Val Arg Ser Lys Ser Phe Leu Gin Val 420 425 430 Cys Cys Cys Val Gly Pro Ser Thr Pro Ser Leu Asp Lys Asn His Gin 435 440 445 Val Pro Thr He Lys Val His Thr He Ser Leu Ser Glu Asn Gly Glu 450 455 460 Glu Val 465

Claims: What is claimed is: 1. A method of treating benign prostatic hyperplasia in a subject in need thereof which comprises administering to the subject a therapeutically effective amount of an a ιc antagonist which binds to a human α lc adrenergic receptor with a binding affinity greater than 50-fold higher than the binding affinity with which the α lc antagonist binds to a human cx lb adrenergic receptor, provided that the α lc antagonist is not 2, 6-Dimethyl-4- (4-nitrophenyl) - 1, 4-dihydropyridine-3, 5-dicarboxylic acid N- [3- (4, -diphenylpiperdin-1-yl) -propyl] amide ester hydrochloride hydrate. 2. The method of claim 1, wherein the α lc antagonist additionally binds to a human a la adrenergic receptor, a human cx 2 adrenergic receptor and a human histamine H x receptor with a binding affinity which is greater than ten-fold lower than the binding affinity with which the o; lc antagonist binds to the cι lc adrenergic receptor. 3. The method of claim 1, wherein the o; lc antagonist binds to the human α lc adrenergic receptor with a binding affinity greater than 75-fold higher than the binding affinity with which the a lc antagonist binds to the human c lb adrenergic receptor. 4. The method of claim 3, wherein the α lc antagonist additionally binds to a human a la adrenergic receptor, a human a 2 adrenergic receptor and a human histamine H-_ receptor with a binding affinity which is greater than ten-fold lower than the binding affinity with which the o; lc antagonist binds to the a lc adrenergic receptor. 5. The method of claim 1, wherein the α lc antagonist additionally binds to a calcium channel with a binding affinity which is greater than ten-fold lower than the binding affinity with which the a lc antagonist binds to the o; lc adrenergic receptor. 6. The method of claim 1, wherein the a lc antagonist additionally binds to a human dopamine D 2 or human histamine H 2 receptor with a binding affinity which is greater than ten-fold lower than the binding affinity with which the ιc antagonist binds to the c ιc adrenergic receptor. 7. The method of claim 1, wherein the α ιc antagonist additionally binds to any serotonin receptor with a binding affinity which is greater than ten-fold lower than the binding affinity with which the α ιc antagonist binds to the α ιc adrenergic receptor. 8. The method of claim 1, wherein the a ιc antagonist additionally binds to a dopamine D 3 , D 4 or D 5 receptor with a binding affinity which is greater than ten-fold lower than the binding affinity with which the o; lc antagonist binds to the ct lc adrenergic receptor. 9. The method of claim 1, wherein the α lc antagonist additionally does not cause a fall in blood pressure at dosages effective to alleviate benign prostatic hyperplasia. 10. The method of claim 9, wherein the α ιc antagonist additionally does not cause a fall in blood pressure in rats at a dosage of 10 micrograms of α ιc antagonist per kilogram per rat. 11. A method of treating benign prostatic hyperplasia in a subject in need thereof which comprises administering to the subject a therapeutically effective amount of an o; lc antagonist which binds to a human α lc adrenergic receptor with a binding affinity greater than 100-fold higher than the binding affinity with which the α ιc antagonist binds to a human α lb adrenergic receptor and a human histamine H x receptor. 12. The method of claim 11, wherein the α lc antagonist additionally binds to a human α la adrenergic receptor and a human α 2 adrenergic receptor with a binding affinity which is greater than ten-fold lower than the binding affinity with which the α ιc antagonist binds to the α lc adrenergic receptor. 13. The method of claim 11, wherein the α ιc antagonist additionally binds to a calcium channel with a binding affinity which is greater than ten-fold lower than the binding affinity with which the α lc antagonist binds to the α lc adrenergic receptor. 14. The method of claim 11, wherein the α ιc antagonist additionally binds to a human dopamine D 2 or human histamine H 2 receptor with a binding affinity which is greater than ten-fold lower than the binding affinity with which the α ιc antagonist binds to the cι lc adrenergic receptor. 15. The method of claim 11, wherein the α lc antagonist additionally binds to any serotonin receptor with a binding affinity which is greater than ten-fold lower than the binding affinity with which the α ιc adrenergic receptor. 16. The method of claim 11, wherein the o; lc antagonist additionally binds to a dopamine D 3 , D 4 or D 5 receptor with a binding affinity which is greater than ten-fold lower than the binding affinity with which the o; lc antagonist binds to the ot lc adrenergic receptor. 17. The method of claim 11, wherein the ot lc antagonist additionally does not cause a fall in blood pressure at dosages effective to alleviate benign prostatic hyperplasia. 18. The method of claim 17, wherein the α ιc antagonist additionally does not cause a fall in blood pressure in rats at a dosage of 10 micrograms of o; lc antagonist per kilogram per rat. 19. A method of treating benign prostatic hyperplasia in a subject which comprises administering to the subject a therapeutically effective amount of an ιc antagonist which: a. binds to a human a ιc adrenergic receptor with a binding affinity greater than 100- fold higher than the binding affinity with which the cι lc antagonist binds to a human lh adrenergic receptor, a human OU 1B adrenergic receptor, and a human histamine H x receptor; and b. binds to a human 2 adrenergic receptor with a binding affinity which is greater than 100-fold lower than the binding affinity with which the a lc antagonist binds to such a lc adrenergic receptor. 20. The method of claim 19, wherein the αt ιc antagonist (a) binds to a human < lc adrenergic receptor with a binding affinity greater than 300-fold higher than the binding affinity with which the a ιc antagonist binds to a human a 1A adrenergic receptor, a human o; 1B adrenergic receptor, and a human histamine K. receptor, and (b) binds to a human o; 2 adrenergic receptor with a binding affinity which is greater than 300-fold lower than the binding affinity with which the o; lc antagonist binds to such α ιc adrenergic receptor. 21. The method of claim 19, wherein the α lc antagonist additionally binds to a calcium channel with a binding affinity which is greater than ten-fold lower than the binding affinity with which the αt ιc antagonist binds to the α; ιc adrenergic receptor. 22. The method of claim 19, wherein the α ιc antagonist additionally binds to a calcium channel with a binding affinity which is greater than 20-fold lower than the binding affinity with which the a ιc antagonist binds to the α ιc adrenergic receptor. 23. The method of claim 19, wherein the α ιc antagonist additionally binds to a calcium channel with a binding affinity which is greater than 50-fold lower than the binding affinity with which the α ιc antagonist binds to the α ιc adrenergic receptor. 24. The method of claim 19, wherein the α ιc antagonist additionally binds to a calcium channel with a binding affinity which is greater than 100-fold lower than the binding affinity with which the α lc antagonist binds to the α ιc adrenergic receptor. 25. The method of claim 19, wherein the α lc antagonist additionally binds to a calcium channel with a binding affinity which is greater than 300-fold lower than the binding affinity with which the α ιc antagonist binds to the o; lc adrenergic receptor. 26. The method of claim 19, wherein the α lc antagonist additionally binds to a human dopamine D 2 or human histamine H 2 receptor with a binding affinity which is greater than ten-fold lower than the binding affinity with which the a ιc antagonist binds to the α ιc adrenergic receptor. 27. The method of claim 19, wherein the o; lc antagonist additionally binds to a human dopamine D 2 or human histamine H 2 receptor with a binding affinity which is greater than 20-fold lower than the binding affinity with which the α ιc antagonist binds to the CU 1C adrenergic receptor. 28. The method of claim 19, wherein the α ιc antagonist additionally binds to a human dopamine D 2 or human histamine H 2 receptor with a binding affinity which is greater than 50-fold lower than the binding affinity with which the α lc antagonist binds to the α ιc adrenergic receptor. 29. The method of claim 19, wherein the α ιc antagonist additionally binds to a human dopamine D 2 or human histamine H 2 receptor with a binding affinity which is greater than 100-fold lower than the binding affinity with which the α ιc antagonist binds to the 0! 1C adrenergic receptor. 30. The method of claim 19, wherein the α ιc antagonist additionally binds to a human dopamine D 2 or human histamine H 2 receptor with a binding affinity which is greater than 300-fold lower than the binding affinity with which the ot lc antagonist binds to the ct ιc adrenergic receptor. 31. The method of claim 19, wherein the ot lc antagonist additionally binds to any serotonin receptor with a binding affinity which is greater than ten-fold lower than the binding affinity with which the oι lc antagonist binds to the < ιc adrenergic receptor. 32. The method of claim 19, wherein the cϋ ιc antagonist additionally binds to any serotonin receptor with a binding affinity which is greater than 20-fold lower than the binding affinity with which the α lc antagonist binds to the o; lc adrenergic receptor. 33. The method of claim 19, wherein the α ιc antagonist additionally binds to any serotonin receptor with a binding affinity which is greater than 50-fold lower than the binding affinity with which the α ιc antagonist binds to the α ιc adrenergic receptor. 34. The method of claim 19, wherein the oι lc antagonist additionally binds to any serotonin receptor with a binding affinity which is greater than 100-fold lower than the binding affinity with which the α ιc antagonist binds to the α ιc adrenergic receptor. 35. The method of claim 19, wherein the α ιc antagonist additionally binds to any serotonin receptor with a binding affinity which is greater than 300-fold lower than the binding affinity with which the α ιc antagonist binds to the α ιc adrenergic receptor. 36. The method of claim 19, wherein the ot lc antagonist additionally binds to a dopamine D 3 , D 4 , or D s receptor with a binding affinity which is greater than ten-fold lower than the binding affinity with which the α ιc antagonist binds to the α ιc adrenergic receptor. 37. The method of claim 19, wherein the a ιc antagonist additionally binds to a dopamine D 3 , D 4 , or D 5 receptor with a binding affinity which is greater than 20-fold lower than the binding affinity with which the ιc antagonist binds to the α ιc adrenergic receptor. 38. The method of claim 19, wherein the cϋ ιc antagonist additionally binds to a dopamine D 3 , D 4 , or D 5 receptor with a binding affinity which is greater than 50-fold lower than the binding affinity with which the α ιc antagonist binds to the a ιc adrenergic receptor. 39. The method of claim 19, wherein the α lc antagonist additionally binds to a dopamine D 3 , D 4 , or D s receptor with a binding affinity which is greater than 100-fold lower than the binding affinity with which the α lc antagonist binds to the α ιc adrenergic receptor. 40. The method of claim 19, wherein the α ιc antagonist additionally binds to a dopamine D 3 , D 4 , or D 5 receptor with a binding affinity which is greater than 300-fold lower than the binding affinity with which the a lc antagonist binds to the α ιc adrenergic receptor. 41. The method of claim 19, wherein the α ιc antagonist additionally does not cause a fall in blood pressure at dosages effective to alleviate benign prostatic hyperplasia. 42. The method of claim 41, wherein the a ιc antagonist additionally does not cause a fall in blood pressure in rats at a dosage of 10 micrograms of α ιc antagonist per kilogram per rat. 43. A method of inhibiting contraction of a prostate tissue in a subject in need thereof which comprises administering to the subject a therapeutically effective amount of an ιc antagonist which binds to a human o; lc adrenergic receptor with a binding affinity greater than 50-fold higher than the binding affinity with which the o; lc antagonist binds to a human ce lb adrenergic receptor, provided that the <x ιc antagonist is not 2, 6-Dimethyl-4- (4-nitrophenyl) - 1, 4-dihydropyridine-3, 5-dicarboxylic acid N- [3- (4, 4-diphenylpiperdin-1-yl) -propyl] amide ester hydrochloride hydrate. 44. The method of claim 43, wherein the α lc antagonist additionally binds to a human o; la adrenergic receptor, a human 2 adrenergic receptor and a human histamine H x receptor with a binding affinity which is greater than ten-fold lower than the binding affinity with which the o; lc antagonist binds to the α; lc adrenergic receptor. 45. The method of claim 43, wherein the a ιc antagonist binds to a human αt lc adrenergic receptor with a binding affinity greater than 75-fold higher than the binding affinity with which the α ιc antagonist binds to the human α lb adrenergic receptor. 46. The method of claim 45, wherein the α: lc antagonist additionally binds to a human la adrenergic receptor, a human a 2 adrenergic receptor and a human histamine E x receptor with a binding affinity which is greater than ten-fold lower than the binding affinity with which the α ιc antagonist binds to the Q! lc adrenergic receptor. 47. The method of claim 43, wherein the α ιc antagonist additionally binds to a calcium channel with a binding which is greater than ten-fold lower than the binding affinity with which the oι lc antagonist binds to the α ιc adrenergic receptor. 48. The method of claim 43, wherein the α ιc antagonist additionally binds to a human dopamine D 2 or human histamine H 2 receptor with a binding affinity which is greater than ten-fold lower than the binding affinity with which the αt lc antagonist binds to the ot lc adrenergic receptor. 49. The method of claim 43, wherein the Q! 1C antagonist additionally binds to any serotonin receptor with a binding affinity which is greater than ten-fold lower than the binding affinity with which the o; lc antagonist binds to the α ιc adrenergic receptor. 50. The method of claim 43, wherein the lc antagonist additionally binds to a dopamine D 3 , D 4 or D 5 receptor with a binding affinity which is greater than ten-fold lower than the binding affinity with which the α ιc antagonist binds to the α ιc adrenergic receptor. 51. The method of claim 43, wherein the lc antagonist additionally does not cause a fall in blood pressure at dosages effective to alleviate contraction of the prostate tissue. 52. The method of claim 51, wherein the α ιc antagonist additionally does not cause a fall in blood pressure in rats at a dosage of 10 micrograms of lc antagonist per kilogram per rat. 53. A method of inhibiting contraction of prostate tissue in a subject in need thereof which comprises administering to the subject a therapeutically effective amount of an α ιc antagonist which binds to a human lc adrenergic receptor with a binding affinity greater than 100-fold higher than the binding affinity with which the a lc antagonist binds to a human ot lb adrenergic receptor and a human histamine H x receptor. 54. The method of claim 53, wherein the α ιc antagonist additionally binds to a human a la adrenergic receptor and a human o 2 adrenergic receptor with a binding affinity which is greater than ten-fold lower than the binding affinity with which the α lc antagonist binds to the α lc adrenergic receptor. 55. The method of claim 53, wherein the oι lc antagonist additionally binds to a calcium channel with a binding affinity which is greater than ten-fold lower than the binding affinity with which the α lc antagonist binds to the α lc adrenergic receptor. 56. The method of claim 53, wherein the α lc antagonist additionally binds to a human dopamine D 2 or human histamine H 2 receptor with a binding affinity which is greater than ten-fold lower than the binding affinity with which the α ιc antagonist binds to the α ιc adrenergic receptor. 57. The method of 53, wherein the α ιc antagonist additionally binds to any serotonin receptor with a binding affinity which is greater than ten-fold lower than the binding affinity with which the xc antagonist binds to the o; lc adrenergic receptor. 58. The method of claim 53, wherein the α ιc antagonist additionally binds to a dopamine D 3 , D 4 or D 5 receptor with a binding affinity which is greater than ten-fold lower than the binding affinity with which the a lc antagonist binds to the lc adrenergic receptor. 59. The method of claim 53, wherein the α lc antagonist additionally does not cause a fall in blood pressure at dosages effective to alleviate contraction of the prostate tissue. 60. The method of claim 59, wherein the α lc antagonist additionally does not cause a fall in blood pressure in rats at a dosage of 10 micrograms of α ιc antagonist per kilogram per rat. 61. A method of inhibiting contraction of a prostate tissue which comprises contacting the prostate tissue with an effective contraction-inhibiting amount of an oι lc antagonist which: a. binds to a human α lc adrenergic receptor with a binding affinity greater than 100-fold higher than the binding affinity with which the α ιc antagonist binds to a human α 1A adrenergic receptor, a human α 1B adrenergic receptor, and a human histamine H x receptor; and b. binds to a human a 2 adrenergic receptor with a binding affinity which is greater than 100-fold lower than the binding affinity with which the α ιc antagonist binds to such c ιc adrenergic receptor. 62. The method of claim 61, wherein the o; lc antagonist (a) binds to a human a ιc adrenergic receptor with a binding affinity greater than 300-fold higher than the binding affinity with which the α ιc antagonist binds to a human oι 1A adrenergic receptor, a human a 1B adrenergic receptor, and a human histamine H x receptor, and (b) binds to a human o; 2 adrenergic receptor with a binding affinity which is greater than 300-fold lower than the binding affinity with which the α ιc antagonist binds to such oι lc adrenergic receptor. 63. A method of inhibiting contraction of a prostate tissue in a subject which comprises administering to the subject an effective contraction-inhibiting amount of an cx lc antagonist which: a. binds to a human c ιc adrenergic receptor with a binding affinity greater than 100-fold higher than the binding affinity with which the α lc antagonist binds to a human o; 1A adrenergic receptor, a human a 1B adrenergic receptor, and a human histamine H x receptor; and b. binds to a human ot 2 adrenergic receptor with a binding affinity which is greater than 100-fold lower than the binding affinity with which the α ιc antagonist binds to such α lc adrenergic receptor. 64. The method of claim 63, wherein the o; lc antagonist (a) binds to a human x lc adrenergic receptor with a binding affinity greater than 300-fold higher than the binding affinity with which the α lc antagonist binds to a human α 1A adrenergic receptor, a human α 1B adrenergic receptor, and a human histamine H x receptor, and (b) binds to a human o; 2 adrenergic receptor with a binding affinity which is greater than 300-fold lower than the binding affinity with which the α; ιc antagonist binds to such oκ lc adrenergic receptor. 65. The use of a compound which: a. binds to a human α lc adrenergic receptor with a binding affinity greater than 100- fold higher than the binding affinity with which the a lc antagonist binds to a human a^ adrenergic receptor, a human oι 1B adrenergic receptor, and a human histamine H- L receptor; and b. binds to a human α 2 adrenergic receptor with a binding affinity which is greater than 100-fold lower than the binding affinity with which the a ιc antagonist binds to such α ιc adrenergic receptor in the preparation of a medicament for treating begin prostatic hyperplasia. 66. The use of a compound which: a. binds to a human α ιc adrenergic receptor with a binding affinity greater than 100- fold higher than the binding affinity with which the α ιc antagonist binds to a human Q! 1A adrenergic receptor, a human α 1B adrenergic receptor, and a human histamine H- L receptor; and b. binds to a human a 2 adrenergic receptor with a binding affinity which is greater than 100-fold lower than the binding affinity with which the a ιc antagonist binds to such ιc adrenergic receptor in the preparation of a medicament for inhibiting contraction of a prostate tissue. 67. A drug which is useful for treating benign prostatic hyperplasia, the effective ingredient of the drug being an a ιc antagonist which: a. binds to a human a ιc adrenergic receptor with a binding affinity greater than 100- fold higher than the binding affinity with which the α lc antagonist binds to a human Q! 1A adrenergic receptor, a human α 1B adrenergic receptor, and a human histamine H-_ receptor; and b. binds to a human 2 adrenergic receptor with a binding affinity which is greater than • 100-fold lower than the binding affinity with which the α ιc antagonist binds to such α lc adrenergic receptor. 68. A drug which is useful for inhibiting contraction of a prostate tissue, the effective ingredient of the drug being an α lc antagonist which: a. binds to a human α ιc adrenergic receptor with a binding affinity greater than 100- fold higher than the binding affinity with which the OU 1C antagonist binds to a human adrenergic receptor, a human α 1B adrenergic receptor, and a human histamine H- L receptor; and b. binds to a human o; 2 adrenergic receptor with a binding affinity which is greater than 100-fold lower than the binding affinity with which the α lc antagonist binds to such a ιc adrenergic receptor.

Inventors: BRANCHEK THERESA A, CHIU GEORGE, FORRAY CARLOS C, GLUCHOWSKI CHARLES, HARTIG PAUL R, WETZEL JOHN M, BRANCHEK, THERESA, A., CHIU, GEORGE, FORRAY, CARLOS, C., GLUCHOWSKI, CHARLES, HARTIG, PAUL, R., WETZEL, JOHN, M.
Applicants: BRANCHEK THERESA A, CHIU GEORGE, FORRAY CARLOS C, GLUCHOWSKI CHARLES, HARTIG PAUL R, SYNAPTIC PHARMA CORP, WETZEL JOHN M, BRANCHEK, THERESA, A., CHIU, GEORGE, FORRAY, CARLOS, C., GLUCHOWSKI, CHARLES, HARTIG, PAUL, R., SYNAPTIC PHARMACEUTICAL CORPORATION, WETZEL, JOHN, M.
Application year: 1995
Main classification: A61K31
IPC codes: A61K31, A61K45