bluuebunny/crossref_metadata_2025 huggingface dataset:
Discriminative stimulus properties of haloperidol
Authors: McElroy John F. , Stimmel Jay J. , O'Donnell James M.
Published: January 2005

Rats (N = 9) were trained to discriminate the antipsychotic drug haloperidol (0.05 mg/kg i.p.) from drug vehicle (0.25% acetic acid in 0.9% saline) using a water‐reinforced, fixed‐ratio 10 response operant procedure. Acquisition of discrimination required a mean of 45 trainingsessions (median value of 38 sessions). The discriminative stimulus was dose‐dependent with an ED50 value of 0.008 mg/kg. The total number of responses per 10‐min test session was significantly reduced at all doses of haloperidol that produced haloperidol lever selection. The antipsychotic drug chlorpromazine substituted for the haloperidol discriminative stimulus (ED50 = 0.38 mg/kg). The indirect dopaminergic agonists amphetamine (1.0 mg/kg) and cocaine (10 mg/kg) fully blocked the haloperidol discriminative stimulus. Taken together, these initial results suggest that the discriminative stimulus produced by haloperidol is mediated, at least in part, by an interaction with dopamine receptors.
Behavioral effects of non‐opioid antitussive anticonvulsants
Authors: Witkin Jeffrey M. , Tortella Frank C.
Published: January 2005

Many of the currently used anticonvulsants possess a host of undesirable pharmacological properties. Several non‐opioid antitussives bind to high‐affinity [3H]dextromethorphan sites in brain and have novel anticonvulsants activity. Because these compounds may be useful in the treatment of some epilepsies, either alone or as adjuncts. Behavioral effects of these as well as clinically used anticonvulsant drugs were studied under a standard preclinical test of sedative‐hypnotic/anxiolytic activity which generally yieds positive results with standard anticonvulsants. Lever‐press responses of male Sprague‐Dawley rats were maintained under a multiple schedule of food presentation in which responses in one component were suppressed by brief electric shock (punishment) whereas responses in an alternate component were not punished. The drug doses tested were the ED50 and 2 X ED50 for anticonvulsant activity against maximal electroshock‐induced convulsions. The non‐opioid antitussive anticonvulsants, carbetapentane, caramiphen, dextromethorphan, as well as diphenylhydantoin, did not increase punished responding, Nonpunished responding was unaffected by ED50 does levels of these compounds. In contrast, diazepam increased punished responding to 800% of control levels and increased nonpunished responding at 1 mg/kg. Responding was typically decreased by the highest doses of all drugs studied except diphenylhydantion. Thus, the non‐opioid antitussive anticonvulsants were devoid of significant behavioral effects at the ED50 does and did not possess the anxiolytic activity of benzodiazepine or barbiturate anticonvulsants.
Antihypertensive activity and effects on blood flow of CL 115,999 (5‐lodo‐5,6‐dihydro‐15‐deoxy‐16‐hydroxy‐16‐vinyl‐prostacyclin methyl ester), a new potent orally and transdermally long‐acting prostacyclin analog
Authors: Chan Peter S. , Cervoni Peter , Ronsberg Margaret A. , Scully Patricia A. , Quirk Gerald J. , McLendon Trina K.
Published: January 2005

CL 115,999 was found to be a very potent orally and transdermally active antihypertensive prostacyclin (PGl2) analog with a long duration of action. In conscious spontaneously hypertensive rats (SHR), CL 115,999 lowered mean arterial blood pressure (MABP) 16, 37, 47, and 54 mm Hg at 0.5, 1, 3, and 10 mg/kg orally, respectively. It lowered MABP 19, 28, and 50 mm Hg at 0.1, 0.3, and 1 mg/kg transdermally with durations of action of 2, >6, and >24 hr, respectively. In aorta‐coarcted, renin‐dependent, malignant hypertensive rats, and in deoxycorticosterone aceate (DOCA)‐salt‐induced (low renin) hypertensive rats, CL 115,999 at 3 mg/kg orally lowered MABP 54 and 66 mm Hg lasting longer than 6 and 5 hr, respectively. In conscious two‐kidney, one‐clip, Goldblatt hypertensive dogs, CL 115,999 decreased MABP 33 and 66 mm Hg at 1 (p.o.), and 0.5 (i.v.) mg/kg, respectively. CL 115,999 increased blood flows to renal, coronary, carotid, femoral, and superior mesenteric arterial beds in anesthetized dog when given intraarterially into the bed under study. These findings suggest that CL 115,999 produces potent vasodilation leading to lowering of blood pressure and may act like endogenous prostacyclin in the vasculatures and may be useful for the treatment of hypertension and other cardiovascular diseases in humans.
Memory impairment induced by CCK‐8 antagonists in passive avoidance response of the rat
Authors: Takashima Akira , Ltoh Shinji
Published: January 2005

The effect of novel potent CCK‐8 antagonists on a one‐trial passive avoidance response was investigated in the rat. Intracerebroventricular administration of L‐364,718 and CR 1409 in doses of 10 ng per rat or more and proglumide in doses of 100 ng per rat or more completely attenuated the passive avoidance response, when examined 24 hr after the injection. The effective doses of these antagonists did not cause any motility change, as tested by an open‐field situation at the same period of time after the central administration. The present findings, together with our previous results on an active avoidance response, suggests that endogenous CCK‐8 may be involved in memory processes.
In vivo hemodynamic effects of endothelium‐derived constricting factor in the dog
Authors: Hom Gary J. , Highsmith Robert F. , Pang David C.
Published: January 2005

Primary cultures of bovine thoracic aortic endothelial cells release an endothelium‐derived constricting factor (EDCF), which contracts isolated porcine, bovine, and canine coronary arteries and increases coronary perfusion pressure in isolated rabbit heart. We have tested the effect of theis EDCF on coronary and aortic flows, left ventricular dP/dt, and left ventricular end diastolic pressure, and mean arterial pressure in opern chest anesthetized dogs. Intracoronary administration of conditioned medium containing EDCF caused a reduction in coronary flow. The constrictor response was slow in onset, peaked 50 min after bolus injection, and was sustained during the rest of the observation period. Aortic flow, heart rate, left ventricular dP/dt, left ventricular end diastolic pressure, and mean arterial pressure were not significantly altered. Intracoronary administration of denatured conditioned medium or nonconditioned medium did not elicit any cardiovascular changes. The EDCF‐induced reduction in coronary flow was inhibited by intracoronary administration of nitroglycerin. These findings suggest that conditioned medium from bovine aortic endothelial cells produces coronary vasoconstriction in the intact, anesthetized dog.
Radioelectroencephalographic characterization of tenilsetam (CAS 997), a putative nootropic compound, in the freely behaving rat
Authors: Dimpfel Wilfried , Spüler Manfred , Schindler Ursula
Published: January 2005

Recording, telemetric trandmission, and spectral analysis of field potentials from frontal cortex, hippocampus, striatum, and reticular formation of the rat brain were used to monitor the effect of tenilsetam (CAS 997) and piracetam on the central nervous in delta and alpha2 power in all brai areas. Dose‐dependent decreases in alpha1 power were seen in the frontal cortex, striatum, and reticular formation, whereas the hippocampal alpha1 activity increased (100 mg/kg) or remained unaffected. These effects were dose‐dependent and lasted for at least 90 min. In the presence of piracetam, changes in brain electrical activity were dominated by an overall decrease in alpha1 activity and by less pronounced effects on beta1 activity. The spectral pattern profile induced by tenilsetam was compared to the “fingerprints” of a great number of different drugs from our data base. Some similarities to the action of fluvoxamine and SK&F 38393 point to changes in serotonergic and dopaminergic transmission. The present data show the functional outcome of interactions with different aspects of neurotranmission and suggest that the “nootropic” drug tenilsetam enhances vigilance by shifting the balance of neurotransmission to a status resembling low serotonergic and, at the same time, high dopaminergic activity. These drugs obviously not only improve brain function under pathological conditions but can also affects electrical activity of the intact brain.
Reversal of chlordiazepoxide‐induced impairment in successive discrimination performance by RO 15‐1788
Authors: Cole Sherwood O.
Published: January 2005

The effects of chiordiazepoxide (CDP) alone and in combination with Ro 15‐1788 on the performance of a previously learned go‐no go successive discrimination were studied in male Sprague‐Dawley rats. CDP 10 mg/kg impaired discrimination performance in six sucessive sessions, with animals showing recovery in two post‐drug sessions. The impairment in disrcimination performance was due to an increase in responding during no go (waiting) periods of the task. The benzodizepine (BDZ) receptor antagonist Ro 15‐778 (5 and 10 mg/kg) reversed the impairment in discrimination performance in sessions 2‐6 (but not 1) when co‐administered with CDP. While the effectiveness of Ro 15‐1788 was not dose‐dependent, the reversal in discrimination impairment was due to a reduction in responding during no go periods of the task. These findings suggest that the impairment in discrimination performance produced by CDP is mediated by central BDZ receptor sites. When administered alone, Ro 15‐1788 10 mg/kg (but not 5mg/kg) produced a mild BDZ‐like impairment in discrimination performance and increase in a no go period responding. These findings suggest that Ro 15‐1788 is not a neutral antagonist but has some intrinsic action of its own.
Tissue plasminogen activator synthesis by trabecular cells and its implications for fibrinolytic therapy of the eye
Authors: Tripathi Ramesh C. , Park James K. , Tripathi Brenda J. , Ts'ao Chunghsin
Published: January 2005

Tissue plasminogen activator (t‐PA) has proved to be an effective drug for intravascular fibrinolysis. We have found that the trabecular meshwork system, which regulates the outflow of the aqueous humor in the eye, normally contains a significant amount of t‐PA (0.2 IU/mg protein). When we experimentally introduced 0.2 ml autologous plasma into the anterior chamber of dog eyes, the amount of t‐PA in the trabecular meshwork increased 2.5‐fold within 90 minutes. In cultured porcine trabecular meshwork cells, exposure to 10 U/ml thrombin for 24 hours caused a maximum rise in the concentration (0.82 ng/ml) and in the activity (0.63 IU/ml) of t‐PA. Despite this synthesis of t‐PA by the trabecular meshwork system and other structures of the eye, as well as its normal level in the aqueous humor, a delay in the dissolution of fibrin in the anterior chamber occurs in various clinical conditions, and this compromises the structural and functional integrity of the ocular tissues. Because the locally produced proteases are apparently insufficent to resolve rapidly the fibrin, and based on our present and previous investigations in the eye, we advocate the exogenous administration of t‐PA when rapid fibrinolysis must be behieved. We propose, with caution, a guideline for the therapeutic use of t‐PA in the eye.
Modification of morphine withdrawal in rats by alterations of the endogenous opioid system: Effects of actinonin and GEMSA
Authors: Dzoljic Eleonora D. , Dzoljic Mihailo R.
Published: January 2005

The results show that actinonin (50‐200 m̈g, i.c.v.), an inhibitor of the three enzymes involved in the biodergradation of enkephalins, attenuates, while guanidinoethylmercaptosuccinic acid (GEMSA 3‐12 m̈g, i.c.v.), an inhibitor of enkephalin‐synthesising carboxypeptidase, aggravates some naloxone‐precipitated withdrawal signs in chronic morphine‐dependent rats. The results suggest that alterations in the functional activity of the endogenous opioid system by drugs that affect enkephalin metabolism might have a significant effect on the severity of opiate withdrawal.
Novel approaches to study myocardial hypertrophy towards development of anti‐hypertensive drugs: Expression of myosin light chain genes during cardiac hypertrophy
Authors: Kumar C. Chandra
Published: January 2005

Myocardial hypertrophy as an adaptive response to various physiological and pathological conditions is characterized by major alterations in the cellular restructuring of the heart as well as by many biochemical and genetic alterations. Hence, the development of hypertrophy provides a unique opportunity to study the various mechanisms underlying the functions of the normal and diseased heart, as well as to understand the molecular mechanisms that operate to regulate cardiac specific gene expression. Both the spontaneously hypertensive rat strain (SHR) and the myocardial cell culture system developed by Paul Simpson have been used as model systems to study cardiac specific gene expression. We have isolated and characterized in detail the rat ventricular specific myosin light chain (MLC)‐1 and MLC‐2 cDNA clones. Using a sensitives S1 nuclease analysis we have shown that while no MLC‐1 mRNA of the ventricular type is detectable in the normal and SHR atrial muscle, there is a selective increase in ventricular MLC‐2 mRNa in both 6 week old (prehypertensive stage) and 18 week old (hypertensive) SHR heart atria. The myocardial cell culture system has been used to examine the effects of α‐adrenergic stimulation on the accumulation of contractile units and the expression of MLC‐2 gene. Stimulation of α‐adrenergic receptors with norepinephrine results in an increase in cellular MLC‐2 protein content as well as an increase in steady‐state level of MLC‐2 mRNA. This increase in MLC‐2 mRNA is mediated in part by an increase in transcription of the MLC‐2 gene. In order to characterize the regulatory elements of the MLC‐2 gene, we have characterized in detail the genomic clone corresponding to rat cardiac MLC‐2 cDNA. The results show a complete conservation of exon and intron organizations between cardiac and skeletal MLC‐2 genes. There is also a strong conservation of DNA sequence elements upstream to the transcription initiation site between rat cardiac and chicken cardiac MLC‐2 genes. Analysis of the cis‐ and trans‐acting factors that regulate MLC‐2 gene expression during cardiac hypertrophy should prove very useful in understanding the molecular mechanisms involved in hypertropic response.
Simultaneous 31P nuclear magnetic resonance spectroscopy and mechanical function in working heart models affected by drugs
Authors: Cohen Sheila M. , Werrmann Jeffrey G. , King Brian W.
Published: January 2005

A working heart model was designed which enabled simultaneous measurement of the physiological function of the heart and the levels of high‐energy phosphates and inorganic phosphate, as well as intracellular pH, by high‐resolution 31P NMR spectroscopy. Careful control of conditions, such as temperature and metallic ions, produced rabbit heart preparations that had stable work output, heart rate, and ATP levels for more than 7 hr. Rat hearts were stable for at least 3 hr. As an example of the utility of the model, the effect of ischemia and two drugs were studied. Global ischemia of a rabbit heart at 36.2°C resulted in almost complete loss of phosphocreatine (PCr) wth 7 min and slower loss of ATP, which reached a plateau at 40% of its initial concentration with 12 min. ntracellular pH fell form 7.01 to 6.03 during 21 min of ischemia. Post‐ischemia, the heart's power output and ATP concentration both returned to about 70% of pre‐ischemia levels, whereas PCr overshot its initial value by 33%. BRL 34915, a K+ channel activator, produced an age‐ and species‐dependent negative inotropic effect in non‐ischemic hearts, with only minor changes in ATP, PCr or pH. In hearts obtained from rats pretreated for 2 days with enalapril, an inhibitor of the angiotensin‐converting enzyme, post‐ischemia power output returned to 74 ± 7% of preischemia levels, compared with 33 ± 11% in hearts from sham‐treated rats (N = 6). Enalapril also lessened the decline of ATP during 20 min of global ischemia and enhanced the recovery of ATP in post‐ischemic hearts (both about 30% greater than control). 31P NMR of working heart preparations enable the effect of drugs and/or ischemia on intracellular energy levels to be determined concurrently with function of the heart. A reproducible method in inducing global ischemia in working hearts facilitates the study of drug effects on functional and metabolic recovery.
Effects of buspirone in the geller‐seifter conflict test with incremental shock
Authors: Howard James L. , Pollard Gerald T.
Published: January 2005

The novel anxiolytic buspirone has weak or inconsistent activity in most of the animal models commonly used to identify anxiolytics. Among the six published studies of the effects of buspirone on punished level‐pressing in the rat, only one reported a clear effect (at two doses), and the peak effect was half that of diazepam. In the present study, in which rats responded for food in Geller‐Seifter conflict procedure with incremental shock, five factors were examined for influence on the effects of buspirone upon punished lever‐pressing: (1) fixed‐ratio 10 vs. fixed ratio 1 in the punishment portion of the multiple schedule, (2) drug‐naive vs. drug‐experienced rats, (3) albino vs. hooded rats, (4) SC vs. PO injection, and (5) time course up to 2 hr. The benzodiazepine chlordiazepoxide robustly increased responding punished by foot‐shock, but under none of the conditions did buspirone produce more than a small, inconsistent increase. Punished level‐pressing in the rat appears not to be an adequate method for identifying buspirone‐like anxiolytics.
Measurement and block of potassium channel currents in the heart: Importance of channel type
Authors: Kass Robert S. , Arena Joseph P. , Walsh Kenneth B.
Published: January 2005

In heart as in other excitable tissues, potassium channel currents play an important role in maintaining the normal cell resting potential and controlling the action potential duration. In this study both theoretical and experimental procedures were used to examine the properties of the cardiac delayed rectifier potassium current (IDR) and the inward rectifier potassium current (IIR) and to determine the role that each plays in the repolarization of the action potential. IIR, a relatively time‐independent current, conducts potassium ions more readily in the inward than outward direction with outward current observed solely over the voltage range of ‐70 through ‐30 mV. Because of this behavior, IIR contributes only to the final stages of action potential repolarization. In contrast, IDR, a time‐dependent current with slow kinetics, conducts potassium ions outward over a broad positive voltage range and thus plays a dominant role in initiating and sustaining repolarization. A number of approaches, including single channel analysis and pharmacological interventions, have been begun to further characterize these two important ion currents.
Current concepts and animal models of sudden cardiac death for drug development
Authors: Chan Peter S. , Cervoni Peter
Published: January 2005

Sudden cardiac death (SCD) or sudden coronary death, occurring in patients with unstable angina (angina at rest), myocardial ischemia with or without myocardial infarction (MI), and congestive heart failure (CHF), emerges as one of the most important challenges in cardiovascular medicine at present. Of the 1.5 million cases of myocardial infarction that occur each year in the U.S., about 540,000 patients will die and more than 300,000 of these will die before they reach a hospital, mostly due to ventricular fibrillation (VF) and/or SCD. About 4.8 million people alive in the U.S. have a history of myocardial infarction, angina pectoris, or both and are prime candidates for SCD. About 3 million people in the U.S. have congestive heart failure (CHF) and about 400,000 new cases are reported each year. One year mortality due to CHF is 33–58% and about 45% of the deaths are sudden. These patients were not those who had deleterious hemodynamic parameters whose demise could be predicted; they were those that died suddenly and unexpectedly of VF. Current pharmacological intervention in patients with a documented myocardial infarction with marketed antiarrhythmic agents has not reduced the overall mortality of SCD significantly. This suggests that an efficacious antiarrhythmic/antifibrillatory agent for the prevention of SCD does not exist at present and that there is an urgent need for such an agent.
Nonclinical regulatory considerations for wound‐healing growth factors
Authors: Weissinger Judi
Published: January 2005

Initial evaluation of the safety of wound‐healing growth factors, whether manufactured by biotechnology or not, is dictated by the extent of knowledge of the physiologic, pharmacologic, and toxicologic effects, in vitro and in vivo in animals, and in man at the proposed dose and duration of administration. Prior to Phase 1 clinical study, products are studied to establish evidence of pharmacologic activity, understand the mechanism of action, evaluate the potential human risk, and establish a clinical study dose range. It is difficult to establish a generic plan and generic protocols for the preclinical development of wound‐healing growth factors because the toxicologic concerns and suggested studies are tailored to the uniqueness of each product. The quantity of useful information which can be gained from preclinical studies is considered for each product on a case‐by‐case basis, taking into account the availability of a relevant model. Preliminary information regarding (1) production of the active moiety, (2) ingredients in the final formulation as it is to be marketed, (3) characterization of the growth factor, (4) the proposed dose and route of administration, (5) the known actions and effects, (6) the similarity to the endogenous growth factors, and (7) the proposed target clinical study population is needed to determine the most appropriate preclinical pharmacological and toxicologic studies. Use of this information and additional data relating the pharmacokinetic and toxicologic profiles will be discussed with respect to generalizations in study concepts for pharmacology and toxicology studies and individualization of these preclinical studies which may occur, based upon the uniqueness of the compound.
Effects of metrifonate, a long‐acting cholinesterease inhibitor, in alzheimer disease: Report of an open trial
Authors: Becker Robert E. , Colliver Jerry , Elble Rodger , Feldman Eleanor , Giacobini Ezio , Kumar Vinod , Markwell Stephen , Morieatry Pamela , Parks Randolph , Schillcutt Samuel D. , Unni Latha , Vicari Sandra , Womack Cindy , Zec Ronald F.
Published: January 2005

This is the first study of a multiple‐dose trial of metrifonate (Met), a long‐acting cholinesterase (ChE) inhibitor, conducted over a prolonged period of time in humans. We have administered Met to 20 patients who met NINCDS‐ADRDA criteria for probable Alzheimer disease (AD). Patients were given, under open conditions, single oral doses of Met. 2.5, 5, 7.5, and 15 mg/kg/wk. A statistically significant improvement in the Alzheimer Disease Assessment Scale (ADAS) scores was observed with the 5 mg/kg/wk dose. Maximal improvement on the ADAS was associated with a mean 55.9% (± 12.6% standard deviation) activity level of red blood cell (RBC) acetylcholinesterase (AChE). Over 80% inhibition of plasma and RBC ChE was achieved with only minor side effects. Cholinesterate inhibition in the CSF of two patients was 37% and 47.5% 24 hr after a second dose of 5 mg/kg/wk of Met separated by 7 days from the first dose.

Twenty‐seven minor side effects were reported: none on 2.5 mg, 5 on 5 mg, 9 on 7.5 mg, and 13 on the 15 mg dose. None of the side effects was clinically significant or drug related or required termination of treatment of dosage adjustment. We conclude that Met is a useful pharmacological probe of cholinergic function in the central nervous system and that double‐blind evaluation of Met in AD is warranted.
Some behavioral effects of repeated d‐amphetamine administrations
Authors: Katz Jonathan L. , Witkin Jeffrey M. , Dworkin Steven I. , Dykstra Linda A. , Carter Richard B.
Published: January 2005

Effects of daily administrations of d‐amphetamine were studied on key peck responses of pigeons maintained under a multiple fixed‐interval 2‐min, fixed‐ratio 30‐responseschedule. Under the fixed‐interval schedule, a pause was followed by a transition to increasing rates of responding until food presentation. Under the fixed‐ratio schedule, higher sustained rates of responding were maintained. Low to intermediate doses (0.3‐1.0 mg/kg) of d‐amphetamine changed the temporal patterns and occasionally increased rates of responding under the fixed‐interval schedule. Higher doses decreased rates of responding under bothschedules. With daily injections of 1.0 mg/kg d‐amphetamine prior to experimental sessions, the effects of this dose on rates and patterns of responding were attenuated, and d‐anphetamine dose‐effect curves were shifted to the right, primarily under the fixed‐ratio schedule. Similar results were obtained with daily presession injections of 5.6 mg/kg d‐amphetamine in a second group of pigeons, except that rates of responding under both schedules were decreased by this daily dose, and did not return completely to control values with repeated injections. In a third group of pigeons, 1.0 mg/kg d‐amphetamine administered daily, after experimental sessions, did not alter dose‐effect functions for d‐amphetamine. In a second experiment, pigeons were trained to peck one response key when given 1.0 mg/kg d‐amphetamine and a different key when given presession water injections. Increasing doses of d‐amphetamine produced incresing percentages of d‐amphetamine‐key responses. Repeated administration of 5.6 mg/kg d‐amphetamine shifted these dose‐effect functions to the right one‐half log unit. Results suggested that decreases in reinforcement frequency are not a necessary condition for the development of behavioral tolerance to d‐amphetamine.
A brief review of atropine effects on physiology and performance
Authors: Penetar David M.
Published: January 2005

Atropine's effects on the eye, visual functions, psychoactivity, and memory and learning are discussed from studies in both nonhuman primates and humans. These effects are discussed in terms of their peripheral and central mediations to provide background information for the behavioral pharmacologist.
In vivo binding properties of non‐sedating antihistamines to CNS histamine receptors
Authors: McQuade Robert D. , Richlan Kimberly , Duffy Ruth A. , Chipkin Richard E. , Barnett Allen
Published: January 2005

A series of antihistamines were examined for their ability to inhibit the in vivo binding of 3H‐mepyramine to mouse brain membranes. All of the seven antihistamines tested inhibited the in vitro binding of 3H‐mepyramine, but loratadine and terfenadine were the only compounds which did not cause an inhibition of the in vivo binding. Conversely, diphenhydramine, chlorpheniramine, astemizole, mequitazine, and cetirizine all resulted in a significant (P < 0.05) decrease in the binding of 3H‐mepyramine, in vivo. These results suggest that loratadine and terfenadine are antihistamines which are unable to cross the blood‐brain barrier and therefore possess a low sedative liability.
In vivo dopamine agonist and antagonist activities of a series of substituted dihydrophenalenes
Authors: Tan Andrew H. , Franklin Stanley R. , Code Robert A. , Althaus John S. , Vonvoigtlander Philip F. , Darlington William H. , Szmuszkovicz Jacob
Published: January 2005

A series of structurally rigid compounds (2‐amino‐2, 3‐dihydro‐3H‐phenalenes) has been synthesized for dopamine (DA) agonist activities. One member (U‐66444B) in the series has been reported as a potent and selective agonist for presynaptic DA receptors. Among close analogues of U‐66444B, we have identified two compounds with DA antagonist activities by behavioral and biochemical endpoints. The distinguishing chemical features of these two antagonists are methyl substitutions on the amino nitrogen and a phenolic hydroxy group having a most proximal position to the amino group. The structure‐activity relationship in this series of compounds may contribute to future design of DA agonists and antagonists.
Inhibition of cardiovascular low‐Km cAMP phosphodiesterase activity by medorinone
Authors: Silver Paul J. , Hamel Linda T. , Bentley Ross G. , Dillon Kathleen , Connell Mary J. , O'Connor Bernard , Ferrari Richard A. , Pagani Edward D.
Published: January 2005

Medorinone (5‐methyl‐1, 6‐naphthyridin‐2(1H)‐one) is a structurally novel cardiotonic/vasodilator agent. The purpose of the present study was to evaluate the effects of medorinone on subcellular systems involved in the contractile‐relaxation processes of cardiac and vascular smooth muscle (VSM); cyclic nucleotide phosphodiesterase (PDE), Ca2+‐regulated contractile proteins, and sarcolemmal Na+‐K+ ATPase. Medorinone produces concentration‐related inhibition (IC50 values between 0.38 and 1.3 μ) of the cGMP‐inhibitable, low‐Km cAMP PDE (peak III PDE from a DEAE‐cellulose column) present in guinea pig and canine cardiac and vascular smooth muscle. The potency of medorinone is similar to that of milrinone and papaverine, less than CI‐930, and greater than imazodan, piroximone, and amrinone. Medorinone is approximately 300–400 × less potent an inhibitor of the low‐Km cAMP PDE. Medorinone appears to be a non‐linear mixed inhibitor of the low‐Km cAMP PDE having a Ki value of approximately 0.3 μM. Medorinone is also an equipotent inhibitor (IC50 values between 0.23 and 0.35 μM) of the low‐m cAMP PDE present in soluble and particulate fractions obtained from normal and myopathic human hearts, with no differences in potency observed between normal and myopathics. Medorinone (10 and 100 μM) does not affect VSM myosin light chain phosphorylation or VSM actomyosin superprecipitation. Moreover, medorinone does not affect cardiac myofibrillar ATPase activity or cardiac sarcolemmal Na+‐K+ ATPase activity. In summary, these data are consistent with the hypothesis that inhibition of the low‐Km cAMP PDE isozyme by medorinone in cardiac and vascular smooth muscle is a mechanism by which this agent produce both positive cardiac inotropy and VSM relaxation.
Effects of arotinolol on regional cerebral blood flow in hypertensive patients with a history of stroke
Authors: Naritomi Hiroaki , Murata Shinji , Shimizu Takao , Nakamura Masaichi , Sasaki Masahiro , Sawada Tohru
Published: January 2005

Although optimal blood pressure control is important for managing stroke patients, the use of antihypertensives in stroke patients often causes cerebral blood flow reduction leading sometimes to deterioration of symptoms. Effects of arotinolol, a β‐blocker with a moderate α‐blocking action, on the regional cerebral blood flow (rCBF) were investigated in 10 hypertensive patients with a history of stroke by using a noninvasive 133Xe inhalation method. The rCBF was measured before and after administration of 15 mg/day arotinolol (three times a day) for 2–3 weeks. After the administration, the blood pressure was reduced in all the patients showing a change in average values of from 176/105 mmHg to 152/90 mmHg. The rCBF in the infarcted and healthy hemispheres was 44.3 ± 4.4 and 44.6 ± 5.0 ml/100 g/min before arotinolol and 44.9 ± 6.4 and 45.3 ± 6.5 ml/100 g/min after arotinolol, respectively. No significant rCBF change was observed after arotinolol in both hemispheres. During the administration, none of the patients suffered from dizziness or other ischemic symptoms. The above results suggest that arotinolol exerts little influence on the cerebral circulation and may be useful for the management of hypertension in stroke patients.
Distribution of GABAA and GABAB receptors in mammalian brain: Potential targets for drug development
Authors: Young Anne B. , Chu Dorothy
Published: January 2005

GABA is the major inhibitory neurotransmitter in mammalian brain. GABA receptors and the metabolism of GABA are significant targets for new centrally acting drugs to treat neurological and behavioral disorders. The simple neutral amino acid is likely to subserve a neurotransmitter role at 25–50% of all synapses in the central nervous system. GABA's actions are mediated by two different receptors, GABAA and GABAB receptors. GABAA receptors are ligand‐gated chloride channels that are sensitive to the convulsant alkaloid bicuculline and modulated by benzodiazepines and barbiturates. GABAB receptors affect calcium and potassium conductance through GTP binding proteins and are insensitive to bicuculline and sensitive to the agonist baclofen. Both receptors are widely distributed in cerebral cortex, hippocampus, basal ganglia, thalamus, cerebellum, and brainstem.
GABAmimetic drugs in hyperkinetic involuntary movement disorders and their effects on mental status
Authors: Tamminga C. A. , Thaker G. K.
Published: January 2005

GABAmimetic drugs are effective in the treatment of hyperkinetic involuntary motor disorders like tardive dyskinesia. Several therapeutic pharmacologic strategies have been identified, including direct‐acting agonists, reuptake blockers, and degradation inhibitors. This pharmacologic response, in addition to providing clinical efficacy data, has led to the speculation that GABA is pathophysiologically involved in tardive dyskinesia. The most potent GABAmimetic compounds have psychotomimetic effects, but some of the weaker GABA agonists are clinically effective for dyskinesias without severe cognitive side effects. Thus, GABA agonists are likely to be available soon as practical treatments for tardive dyskinesia.
New class of hallucinogens: GABA‐enhancing agents
Authors: Hollister Leo E.
Published: January 2005

Hallucinogenic drugs are of interest to psychiatrists as possible models of schizophrenia. Possibly some of the mechanisms by which these drugs elicit altered mental states might lead to a better understanding of schizophrenia. GABA‐enhancing drugs, such as muscimol and CI‐966, produce mental states that differ in various ways from those of other hallucinogens. The mechanism of action also differs from the others, which may be mediated by receptors for serotonin (LSD), acetylcholine (scopolamine), or NMDA (phencyclidine). Whether the GABAA receptor will provide clues to schizophrenia remains to be elucidated.
Magnesium aspartate HCl and magnesium chloride hexahydrate OROS: Comparative absorption of magnesium in dogs
Authors: Coram Willie Mae , Foster Clarence E. , Senft Carl J. , Douglas Frank L. , Weiss George B.
Published: January 2005

The absorption of magnesium (Mg2+) was measured after oral administration to dogs as a sustained‐release MgCl2·6H2O OROS formulation (MgCl2) or as magnesium aspartate hydrochloride (MAH). The compounds and their respective placebos were given at five 90 min intervals in 7.5 mEq doses (sequential protocol) or in ascending daily doses of 7.5, 22.5, and 45 mEq over 3 days (ascending protocol). Urinary excretion of Mg2+ over 24 hr was significantly increased compared to placebo in the dogs given sequential MgCl2 or MAH and was two‐fold greater in the MgCl2‐treated group compared to the MAH group. Plasma Mg2+ increased more rapidly in the MgCl2‐treated dogs but was identical in both groups 1 hr after the fifth sequential dose. Ascending daily doses of MgCl2 and MAH increased urinary Mg2+ and plasma Mg2+ maximally 2–4 hr after each dose; the magnitude of the effect was dose‐dependent in the MgCl2 group. Sequential doses of MgCl2 or MAH increased urinary Ca2++ excretion by 1.06 and 1 mEq/24 hr respectively while the ascending doses of 22.5 and 45 mEq MgCl2 produced significantly greater urinary Ca2+ excretion than the same doses of MAH. Plasma Ca2+ was not changed by either Mg2+ salt in either dose regimen. The data indicate that Mg2+ is readily absorbed after oral administration in the form of either MgCl2 or MAH, but MgCl2 is absorbed more rapidly. Increased urinary excretion of Ca2+ after MgCl2 or MAH may reflect a displacement of tissue Ca2+ by Mg2+.
5‐HT1D serotonin receptors: Results of a structure‐affinity investigation
Authors: Glennon Richard A. , Ismaiel Abd M. , Chaurasia Chandra , Titeler Milt
Published: January 2005

As a prelude to the design of 5‐HT1D agents, we systematically investigated the structure‐affinity relationships for the binding of indolealkylamines and related derivatives at 5‐HT1D serotonin receptors. The results of the investigation reveal that (a) methylation of a 5‐hydroxyl group decreases affinity by 2‐fold, (b) replacement of a 5‐hydroxyl group by hydrogen reduces affinity by an order of magnitude, (c) α‐methylation of the side chain reduces affinity by approximately 50‐fold, (d) N,N‐dimethylation decreases affinity by 4‐fold, (e) methylation at the 2‐position reduces affinity by 300‐fold, (f) small alkyl substituents are not well tolerated at the C7‐ and N1 ‐Positions, (g) shortening of the side chain by one methylene unit reduces affinity by two orders of magnitude, (h) cyclization of the side chain to a β‐carboline dramatically reduces affinity, and (i) the 5‐hydroxy group can be replaced by a carboxamido, benzyloxy, or chlorobenzyloxy moiety without any decrease in affinity. These studies led to the evaluation of certain non‐indolealkylamines and to the finding that (a) simple phenylalkylamines and phenylpiperazines bind with low affinity, but that their benzfused counterparts bind with significantly higher affinity, and (b) the 7‐methoxy analog of 1‐(1‐naphthyl)piperazine (7‐OMe 1‐NP) binds at 5‐HT1D sites with an affinity (Ki = 2 nM) comparable to that of serotonin itself. Various leads were developed that might aid the subsequent design of 5‐HT1D‐selective agents.
Serotonin uptake blockers inhibit the firing of presumed serotonergic dorsal raphe neurons in vitro
Authors: Rigdon Greg C. , Wang Ching M.
Published: January 2005

Some antidepressant drugs are potent inhibitors of neuronal uptake of serotonin. In vivo, these compounds inhibit serotonergic dorsal raphe neuronal firing rates, presumably through increased stimulation of 5‐HT1a autoreceptors. We recorded from electrophysiologically identified serotonergic dorsal raphe neurons in rat brain slices and determined the effects of five serotonin uptake blockers on the firing rates of these units in vitro. Each drug decreased the neuronal firing rates in a concentration‐dependent manner. IC50 values derived from concentration‐response curves are: fluvoxamine, 0.8 μM; sertraline, 1.1 μM; imipramine, 2.7 μM; chlorimipramine, 2.8 μM; and fluoxetine, 4.2 μM. Exposure of brain slices to 10 μM tetrabenazine, a serotonin depleting agent, prior to treatment with serotonin uptake blockers resulted in a rightward shift of the concentration‐response curve. In vitro single unit recording allows: (1) direct comparison with neurochemical data obtained in vitro; (2) access to tissue bypassing blood brain barrier and liver enzymes; (3) quick wash out of drug from tissue; and (4) ability to record from single unitsover long periods (hours). This in vitro test provides a fast, simple means of determining neurophysiological effects of potential antidepressant drugs on the serotonin system.
Neurochemical and in vivo pharmacological profile of sertindole, a limbic‐selective neuroleptic compound
Authors: Sánchez Connie , Arnt Jørn , Dragsted Nils , Hyttel John , Lembøl Hanne Løve , Meier Eddi , Perregaard Jens , Skarsfeldt Torben
Published: January 2005

Sertindole (5‐chloro‐1‐(4‐fluorophenyl)‐3‐[1‐[2‐(2‐imidazolidinon‐1‐yl)ethyl]‐4‐Piperidyl]‐1H‐indole) is a new neuroleptic with a very high selectivity for dopamine (DA) neurones in the ventral tegmental area compared to DA neurones in substantis nigra pars compacta (Skarsfeldt, T., and Perregaard, J. Eur. J. Pharmacol. 182:613–614, 1990). Neurochemical and behavioural effects of sertindole have been investigated in comparison with the classical neuroleptics haloperidol and fluphenazine and the atypical neuroleptic clozapine. In vitro sertindole has high affinity for serotonin S2 (5‐HT2) receptors, DA D‐2 receptors, and α1‐adrenoceptors, moderate affinity for DA D‐1 receptors; low affinity for α2‐adrenoceptors, histamine H1 receptors and sigma receptors; and no affinity for 5‐HT1A, muscarine cholinergic receptors, and β‐adrenoceptors. The in vivo pharmacology is atypical, i.e., a remarkably weak or no effect in acute tests for DA antagonism, and the cataleptogenic potential is very low. Sertindole shows a very potent and long‐acting antagonism at central as well as peripheral 5‐HT2 receptors. The antagonistic effect at peripheral α1‐adrenoceptors is relatively weak in comparison with the 5‐HT2 antagonistic potency in vivo and in vitro. Sertindole shows no anticholinergic effects. In conclusion the pharmacological profile suggests that sertindole is an atypical neuroleptic compound with a low potential for extrapyramidal, autonomic, and anticholinergic side effects.
Antiarrhythmic effects of a novel Na+ and Ca++ channel blocker, SD‐3212: A comparison with its enantiomer (SD‐3211)
Authors: Miyawaki Nobuaki , Yamazaki Fumiko , Furuta Tatsuji , Shigei Tatsuro , Yamauchi Hideyasu
Published: January 2005

The electrophysiological and antiarrhythmic effects of a structurally novel compound, SD‐3212, were evaluated in comparison with its enantiomer (SD‐3211). In isolated guinea pig ventricular muscles, SD‐3212 reduced the maximum upstroke velocity and the plateau phase of action potential in a concentration‐dependent manner, while SD‐3211 significantly affected only action potential duration. SD‐3212 had oral prophylactic effects against both ouabain‐induced (in guinea pigs) and chloroform‐induced (in rats) arrhythmas, whereas SD‐3211 and verapamil were effective only on the former arrhythmia model and mexiletine was effective only on the latter. These results suggest that there is an enantiospecific interaction with cardiac Na+ and Ca++ channels, and that the dual inhibitory action of SD‐3212 on these channels may contribute to its antiarrhythmic properties.
Relationship between structure and efficacy at central benzodiazepine receptors for a series of imidazopyrimidines and imidazoquinolines
Authors: Gardner Colin R. , Budhram Paula , Deacon Robert M. J. , Thomson T. Andrew
Published: January 2005

The efficacy of a series of novel imidazoquinolines and imidazopyrimidines at benzodiazepine (BDZ) receptors was assessed using in vivo models: food‐motivated conflict in rats, stress‐induced ultrasounds in rat pups, leptazol seizures in mice, and suprahyoid muscle twitching in urethane‐anaesthetized rats. Compounds showing activities similar to classical BDZs (anxiolytic, anticonvulsant, and central nervous system (CNS) depressant activities, as well as depression of twitching) have been classified as strong agonists while those showing reduced CNS depressant effects, or reduced anticonvulsant effects with an antagonist profile in twitching, have been classified as moderate and weak partial agonists, respectively. Compounds were regarded as weak or strong inverse agonists according to their abilities to potentiate both seizures and twitching at doses which antagonize full BDZ agonists in the models of anxiety. Modification of two regions of these molecules caused changes in their efficacies. Agonist efficacy following modification to position 2 gave the ranking: oxadiazole > benzoyl > > cyclopropyl ketone ≧ thiazole with the latter compounds becoming inverse agonists in some cases, depending on other changes to the structure. The imidazoquinolines were stronger agonists than the imidazopyrimidines. As the 5,6‐substitutions on the imidazopyrimidines were reduced, compounds possessed less agonism and more inverse agonism, giving the agonism ranking 5‐methyl, 6‐allyl > 5‐methyl, 6‐ethyl > 5,6‐tetramethylene > 5‐ethyl,6‐H ≧ 5‐methyl,6‐H. Combination of the effects of modification of these two regions of the molecules has yielded a scheme which predicts the efficacy of individual members of the series. This scheme has been used to design other molecules with specific efficacies for BDZ receptors in this and other chemical series.
Bidirectional efficacy at benzodiazepine receptors of a series of imidazopyrimidines illustrated in drug discrimination studies
Authors: Gardner Colin R. , Budhram Paula
Published: January 2005

Male Lister rats were trained to discriminate either chlordiazepoxide (CDZP), the benzodiazepine (BDZ) receptor partial agonist RU32698, or leptazol from vehicle on a fixed ratio 20 schedule. From 10 imidazopyrimidine BDZ receptor ligands tested four showed the profiles of agonists in that they substituted for CDZP and RU32698 and antagonized the leptazol cue. RU33203 depressed rates of responding in tests with all three cues, RU32698 only depressed responding at the highest dose in tests in the leptazol cue, and RU33543 or RU32514 did not alter rates of responding. Antagonism of the leptazol cue by RU32514 showed a 50% maximum. These data suggest that the agonist efficacies of these compounds rank RU33203>RU32698>RU33543>RU32514. The other six compounds showed inverse agonist profiles as they antagonized the CDZP cue and substituted for leptazol. Three compounds tested also antagonized the RU32698 cue. RU34113 was equipotent in antagonizing the CDZP cue and substituting for leptazol. RU33094 and RU34134 were clearly more potent in antagonizing the CDZP cue while RU33697, RU33356, and RU34000 showed intermediate profiles. All six compounds decreased rates of responding at doses that maximally antagonized the CDZP cue. These data suggest that RU34113 has the strongest inverse agonist efficacy and RU33094 and RU34134 the weakest efficacy. Structure‐efficacy relationships within this series of imidazopyrimidines are discussed.
Comparison of the stimulus effects of ethylketocyclazocine in fischer and Sprague‐Dawley rats
Authors: Locke Kenneth W. , Gorney Barbara , Cornfeldt Michael , Fielding Stuart
Published: January 2005

The discriminative stimulus effects of ethylketocyclazocine (EKC) were characterized in Fischer and Sprague‐Dawley rats trained to discriminate 0.3 mg/kg of EKC (s. c.) from saline in a two‐choice, discrete‐trial avoidance paradigm. The putative mu‐opioid receptor agonists morphine and fentanyl, as well as the putative kappa‐opioid receptor agonists EKC and U50,488H generalized completely with the EKC cue in both strains of rats. Only small quantitative differences between strains were observed in the generalization of these agonists with EKC. However, Sprague‐Dawley rats were notably more sensitive than Fischer rats to the depressant effects of fentanyl. Only small quantitative differences between strains were also observed in the dose of naloxone necessary for complete antagonism of the EKC‐like stimulus effects of the mu‐ and kappa‐opioid agonists. The mu‐opioid agonists were approximately 2–6 times more sensitive to naloxone antagonism than the kappa‐opioid agonists in both Fischer and Sprague‐Dawley rats. However, due to inter‐animal variability, this difference was not statistically significant. The results of this study suggest that one or more opioid receptor subtype(s) may be involved in the production of the EKC cue in both strains of rats.