bluuebunny/crossref_metadata_2025_split huggingface dataset:
Enzyme inhibition as a source of new drugs
Authors: Kalman Thomas I. 
Published: January 2005

AbstractThe significance of enzymes as targets of drug action is discussed. New approaches to the rational design of enzyme inhibitors are characterized by a pronounced shift of emphasis toward the targets of drug action, as the structure and function of an increasing number of enzymes are described in great detail. The most promising of the recently developed approaches is the design of mechanism‐based enzyme inhibitors and, in particular, suicide inactivators. These require enzymic activation of “latent” functional groups to chemically reactive species. The various functionalities currently encountered are reviewed, grouped into chemical categories.The various aspects of the selectivity and the specificity of mechanism‐based enzyme inhibitors, as well as the stability of drug‐enzyme complexes, are discussed in detail. Reversible covalent bond formation is demonstrated by the recovery of thymidylate synthetase activity after inactivation by various 5‐substituted pyrimidine analogs, using purified bacterial enzyme preparations or intact mammalian cells. The fragmentation and secondary reactions of the inhibitor within the complex are described using typical examples of the action of penicillin on its targets and clavulanate on /3‐lactamase, respectively.The perspectives of enzyme inhibitory drug development are discussed, and some of the many areas currently undergoing rapid exploration are mentioned.It is concluded that the rational design of enzyme inhibitors will play an ever‐increasing and significant role in new drug discovery and development.
Effect of a new eburnamenine derivative (RU 24722) on EEG recovery in the conscious gerbil after cerebral ischemia
Authors: Barzaghi Fernando , Dragonetti Marco , Robert Boissier Jacques 
Published: January 2005

AbstractThe efficacy of a new eburnamenine derivative (RU 24722) on cerebral insufficiency was studied by evaluation of postischemic EEG recovery in the conscious gerbil. Ischemias of different durations were obtained by clamping both common carotids. This method required only brief anesthesia, thereby permitting the recording of EEG recovery in unanesthetized and unrestrained animals during the 24 hr following arterial occlusion. The EEG was analyzed by the Fast Fourier Transform. Mortality rate and clinical status were also evaluated. After a 5‐min ischemia the initial return of EEG was characterized by very high amplitude slow waves (1–2 Hz) and the EEG became normal 24 hr after ischemia. No mortality was observed. After a 10‐min ischemia the early recovery phase was characterized by a decrease in the power spectrum and a rebound of slow frequency waves after 2–4 hr. After 24 hr the EEG was not yet completely normal and 1 animal out of 10 died. A 15‐min ischemia killed 50% of the animals, and the EEGs of the survivors were abnormal even after 24 hr. Treatment with RU 24722 (10 mg/kg/s.c.) significantly improved the electrocortical recovery of gerbils submitted to a 10‐min ischemia. In this group the EEG was normalized 6 hr after ischemia in the same way as in the controls submitted to a 5‐min ischemia. These findings suggest that RU 24722 may have a therapeutic effect in cerebral insufficiency.
An automated descending rate‐intensity self‐stimulation paradigm: Usefulness for distinguishing antidepressants from neuroleptics
Authors: Goldstein Jeffrey M. , Malick Jeffrey B. 
Published: January 2005

AbstractRats with medial forebrain bundle electrodes were trained to self‐stimulate during successive no‐cue periods in which the stimulating current remained constant for the first ten minutes and then decreased in small steps every two minutes for the next 30 minutes. Control response profiles generated in this manner were compared to drug dose‐response profiles. Tricyclic anti‐depressants (imipramine, amitriptyline) and neuroleptics (chlorpromazine, haloperidol) suppressed intracranial self‐stimulation (ICSS) responding in the fixed (F) and descending (DES) current periods. However, in combination with amphetamine, antidepressants potentiated amphetamine's effect in the DES periods only, whereas neuroleptics blocked amphetamine's effect in the DES periods. Both classes of drugs blocked amphetamine's effect in the F period. On the basis of these results, it is suggested that the ICSS model presented in this report can distinguish between antidepressant and neuroleptic drugs.
Influence of neuroleptics on pharmacokinetic parameters of amphetamine in rat after single and double injections
Authors: Shah Nandkumar S. , Shah Arunkumar B. , Patel V. O. 
Published: January 2005

AbstractSprague‐Dawley rats (90–100 g) were injected i.p. with saline, iprindole (10 mg/kg), clozapine (10 mg/kg), pimozide (10 mg/kg), or molindone (10 mg/kg), and 30 min later with dextro‐3H‐amphetamine (5 mg/kg). For two dose studies, a second injection of 3H‐amphetamine (5 mg/kg) was administered 3 hr after the first dose in saline or iprindole pretreated rats. In both studies, brain and hepatic levels of amphetamine paralleled the plasma levels, were highest at 1 hr in single dose and at 4 hr in two dose study, and thereafter, started declining. Iprindole markedly increased tissue amphetamine levels in single dose experiments and further raised and prolonged them up to 24 hr in two dose experiments. Both pimozide and molindone significantly enhanced amphetamine levels, and this effect lasted for 1 and 3 hr, respectively (single dose study); clozapine was ineffective. From the data, it appears that several chemically unrelated neuroleptics alter the distribution and elimination of amphetamine; such alterations need to be assessed in clinical situations, since neuroleptics are used in amphetamine intoxication.
Hypnotic benzodiazepines: Relationship between sleep parameters and pharmacokinetics of loprazolam
Authors: Krieger J. , Perianu M. , Bertagna C. , Mangin P. , Kurtz D. 
Published: January 2005

AbstractIn the search for a relationship between subjective and electrophysiologic sleep parameters and blood levels of loprazolam during night sleep after single and repeated administration, eight normal volunteers took loprazolam, a novel imidazo‐benzodiazepine, on eight consecutive evenings. The assessment of the pharmacokinetics of the drug was done by two different methods: a high‐pressure liquid chromatography‐gas chromatography (HPLC‐GC) measuring the parent drug specifically and a radioreceptor assay (RRA) measuring both the parent drug and the metabolites binding to the benzodiazepine‐receptor; the latter gave slightly higher values indicating the existence of metabolites binding to the benzodiazepine‐receptor. The elimination half‐life of the parent drug was about eight hr and did not significantly increase after repeated administration; the half‐life when using the RRA was some‐what longer since steady state was not reached until the fourth day. A relationship was looked for between pharmacokinetic data and either self‐evaluated or polygraphic sleep parameters obtained from all‐night recordings on the first and eighth treatment nights. No correspondence could be demonstrated, suggesting that the drug does not act directly on sleep systems and that its hypnotic effects may be indirect, secondary to anxiolytic effects or to deactivation of wake systems.
Effects of UP 614‐04, a potential antidepressant, on cerebral monoamine oxidase activity
Authors: Cloarec Alix , Chevalier Ghislaine , Delchambre Chantal , Tremblay Dominique 
Published: January 2005

AbstractThe effects of UP 614‐04, a potential antidepressant agent, and those of some known antidepressant agents on cerebral monoamine oxidase (MAO) activity were compared in rats and mice. Using ex vivo and in vitro techniques, it was shown that UP 614‐04, a viloxazine analogue, inhibited cerebral MAO activity in rats and mice ex vivo, but that it was not effective in vitro. Time‐course studies revealed that the action of UP 614‐04 was more sustained than that of viloxazine, but much less potent or sustained than those of pargyline or isocarboxazide. The effect of UP 614‐04 was not selective to the A or B forms of MAO.
Effect of 3‐PPP, a putative dopamine autoreceptor agonist, on [3H]ligand binding to dopamine receptors of calf and rat striatum
Authors: Wong David T. , Threlkeld Penny G. , Reid Leroy R. 
Published: January 2005

Abstract3‐(3‐Hydroxyphenyl)‐N‐n‐propyliperidine (3‐PPP) is most effective in inhibiting [3H]apomorphine binding in rat striatal membranes, with Ki values of 63 nM. 3‐PPP was six to 27 times less effective when it competed with the binding of [3H]dopamine or [3H]spiperone in calf and rat striatal membranes. At concentrations up to 10 μM, 3‐PPP failed to substitute for dopamine in the activation of adenylate cyclase in rat striatal membranes. 3‐PPP at 4.8‐5 μM caused 50% inhibition of catecholamine uptake in synaptosomes of corpus striatum and hypothalamus, therefore appearing to be a relatively weak uptake inhibitor. The higher affinity of 3‐PPP for [3H]apomorphine binding sites is consistent with its binding to a subset of dopamine receptors which are characterized by a high affinity for both the agonist and antagonist of dopamine.
Perspectives on the in vitro evaluation of anti‐anaphylactic agents
Authors: Weinryb Ira , Coutts Stephen M. , Khandwala Atul S. 
Published: January 2005

AbstractIn vitro models of anaphylaxis such as the release of mediators from the mast cell can do more than identify compounds with intrinsic anti‐allergic activity; they have the potential for development of a detailed profile of activity that may be compared and contrasted in several ways to that of disodium cromoglycate. These parameters include effects upon (a) immunologic versus nonimmunologic release, (b) IgE‐ versus IgG‐provoked release, (c) timing of compound addition relative to challenge, (d) repeated administration (presence or absence of tachyphylaxis), (e) wash‐out of agent (reversibility), and (f) other granulocyte models relative to the mast cell. Use of in vitro models of anaphylaxis in this way allows an early judgment to be made about the extent to which a new compound presents a novel anti‐allergic profile.
A comparison of naloxone and naltrexone in laboratory tests predictive of antipsychotic potential
Authors: Malick Jeffrey B. , Herman Raymond L. , Goldstein Jeffrey M. 
Published: January 2005

AbstractNaloxone and naltrexone were compared neuropharmacologically, especially in several rodent models considered to be predictive of antipsychotic activity, since narcotic antagonists have been reported to be effective in the treatment of schizophrenia. Naltrexone was found to be a potent antagonist of amphetamine‐induced aggregate toxicity in mice; this was in marked contrast to naloxone, which enhanced amphetamine's toxicity. Both naloxone and naltrexone exhibited an unusual profile of activity in the apomorphine‐induced stereotypy test in mice in that they antagonized the chewing behavior but failed to antagonize the rearing; this is in contrast to the activity of standard neurolepitcs (e.g., haloperidol, clozapine) which antagonize both behaviors induced by apomorphine. Neither of the narcotic antagonists exhibited any activity in several other tests predictive of antipsychotic activity. Naltrexone was a potent inhibitor of spontaneous locomotor activity in mice; naloxone, although much weaker, also antagonized motor activity. Thus, endorphins may play a role in the modulation of exploratory or locomotor activity. The marked difference in activity between the two antagonists in the amphetamine aggregate toxicity study may indicate a significant neuropharmacological difference between these agents; i.e., naltrexone may be much more than merely a more potent naloxone. Furthermore, naltrexone's potent activity as an antagonist of amphetamine‐induced aggregate toxicity in mice may be predictive of a better therapeutic effect in schizophrenia than has been observed with naloxone.
Some in vitro and in vivo studies of a new angiotensin I‐converting enzyme inhibitor [[S‐(R*), S*]‐1‐[(3‐acetylthio)‐3‐benzoyl‐2‐methylpropionyl]‐L‐proline] (CL 242,817) in comparison with captopril
Authors: Lai F. M. , Cervoni P. , Tanikella T. , Shepherd C. , Quirk G. , Herzlinger H. , Stubbs C. S. 
Published: January 2005

AbstractSome in vitro and in vivo properties of CL 242,817, a new angiotensin l‐converting enzyme (ACE) inhibitor, were studied and compared to those of captopril. In vitro CL 242,817 effectively inhibited rabbit lung ACE (IC50 54.9 nM), angiotensin l (Al)‐induced contractions (IC50 0.82 μM), and potentiated bradykinin (BK)‐induced contractions (EC50 0.383μM) of the guinea pig ileum. In these systems, CL 242,817 was approximately 3.5, 27, and 96 times less effective than captopril, respectively. In vivo, equimolar oral doses of CL 242,817 (8.36 mg/kg) and captopril (5 mg/kg) were equieffective in inhibiting the pressor responses to intravenously (i.v.) administered angiotensin l (Al) in normotensive rats and dogs. Similar equimolar oral doses of CL 242,817 and captopril were also equieffective in potentiating the depressor responses to i.v. administered BK in the rat. In the anesthetized dog 30 min after dosing, captopril (0.5 mg/kg i.v.) produced significantly greater potentiation of the BK response than a similar dose of CL 242,817. A single 1 mg/kg i.v. dose of Cl 242,817 or captopril effectively lowered mean arterial blood pressure of the aortic‐coarcted hypertensive rat (AHR) and markedly inhibited serum ACE activity after 1 hr. Serum from AHR treated with CL 242,817 or captopril exhibited an apparent loss in ACE inhibition upon cold storage. However, the loss of inhibition of ACE activity was faster with captopril than with CL 242,817. Kinetic studies indicate that CL 242,817 is a pure competive inhibitor of ACE with an estimated Ki of 24.3 nM.
Effect of chronic antidepressant treatment on α2‐adrenoreceptors
Authors: Sethy Vimala H. , Carlsson Robert W. , Harris Douglas W. 
Published: January 2005

AbstractThe effect of chronic (7‐day) intravenous infusion of antidepressants and psychostimulants like cocaine and amphetamine on density of presynaptic α‐adrenergic receptors (α2‐receptors) in rat cerebral cortex and brainstem has been investigated in this study. Antidepressants, cocaine, and amphetamine had no significant effect on the density of α2‐receptors either in the cerebral cortex or brainstem. The results have been discussed with respect to the role of noradrenergic system in regulation of α2‐receptors.
Has thioridazine a role in the treatment of anxious depressed neurotic outpatients?
Authors: Becker Robert E. 
Published: January 2005

AbstractA 4‐wk double‐blind comparison of amitriptyline vs. thioridazine was conducted in 54 anxious depressed patients. Both drugs showed essentially equal efficacy in relieving target symptoms. Thioridazine may have a clinical role in the treatment of anxious depressive symptoms in selected patients.
Psychopharmacological profile of clenbuterol
Authors: Francès H. , Poncelet M. , Danti S. , Goldschmidt P. , Simon P. 
Published: January 2005

AbstractClenbuterol, a β‐adrenergic agonist known to enter the brain, has been studied in mice with a set of psychopharmacological tests. Clenbuterol has an ambiguous sedative effect: it reduces motor activity in a dose‐dependent manner without modifying exploratory behavior in the open field; it does not potentiate the effect of pentobarbital. Clenbuterol decreases the search for food in starved mice. Regarding the tests in animals which are expected to reflect antidepressant activity in man (hypothermias induced by reserpine, oxotremorine or a high dose of apomorphine, potentiation of yohimbine toxicity) clenbuterol acts at doses much lower than those required with two other β‐adrenergic agonists, isoproterenol and salbutamol. Moreover, the active doses of clenbuterol and salbutamol being nearly the same at a peripheral level, the ratio of the centrally and peripherally active doses is highly in favor of clenbuterol. This suggests that the effects of clenbuterol on depressed patients should be studied.
Some neurochemical properties of pramiracetam (CI‐879), a new cognition‐enhancing agent
Authors: Pugsley Thomas A. , Shih Yu‐Hsin , Coughenour Linda , Stewart Sheila F. 
Published: January 2005

AbstractThe present study was initiated to examine the effect of pramiracetam sulfate [N‐[2‐[bis(1‐methylethyl)amino]ethyl]‐2 oxo‐1‐pyrrolidineacetamide sulfate (1:1)] (PR), a new cognition‐activator agent, on various neurochemical parameters in order to gain some insight into the mechanism of action of this agent. PR (100 mg/kg i.p.) did not alter the concentration of norepinephrine, dopamine (DA), serotonin (5‐HT), 5‐hydroxyindoleacetic, and homovanillic acid in various brain areas. The agent also did not alter d‐methamphetamine‐induced changes in monoamine metabolism nor prolactin concentration in rat serum. PR did not exhibit any affinity in vitro for dopaminergic, adrenergic, serotoninergic, GABAergic, muscarinic, adenosine (IC50 > 10 μM), and benzodiazepine receptors (IC50 > 1 μM) binding sites. It may be concluded that the mechanism of action of pramiracetam does not appear to be due to a direct action upon DA and 5‐HT neurotransmitter systems or various brain receptors. PR (44 and 88 mg/kg i.p.) caused a significant increase in the rate of sodium‐dependent high‐affinity choline uptake (HACU) into rat hippocampal synptosomes in vitro. This was specific as no effect was observed in cerebral cortex and corpus striatum. These results would seem to indicate that PR is accelerating hippocampal acetylcholine turnover and thus septal‐hippocampal cholinergic neuronal impulse flow. This effect could be at least partially responsible for the enhancement of cognition processes observed for this agent.
Biochemical characterization of the enantiomers of the novel ergoline dopamine agonist 6‐ethyl‐9‐oxaergoline (EOE)
Authors: Williams Michael , Jones James H. , Watling Keith J. 
Published: January 2005

AbstractThe enantiomers of the novel oxaergoline dopamine (DA) agonist, 6‐ethyl‐9‐oxaergoline (EOE) were compared with the parent recemate for their interactions with dopamine and other monoamine receptor systems in mammalian and teleost nervous tissue. The (−)enantiomer of EOE was over 100 times more active in displacing [3H]apomorphine than the (+)isomer, and 70 times more active in displacing [3H]spiperone. The (−)isomer also exhibited greater binding affinity at serotonin‐1 and ‐2 receptors than the (+)isomer. In contrast, however, the α1‐ and α2‐adrenoceptor activity of the compound resided in the (+)isomer, the latter being some 32 times more active at α2 than α1 adrenoceptors. Examination of EOE in the DA‐sensitive adenylate cyclase system of carp retina showed that while the (−)enantiomer was a partial agonist some 30 times less active than dopamine, the (+)enantiomer was devoid of activity in this D‐1 coupled system at concentrations up to 300 μM.
Cholinomimetic and anticholinergic drugs used to investigate an acetylcholine hypothesis of affective disorders and stress
Authors: Janowsky David S. , Risch Samuel Craig 
Published: January 2005

AbstractThe cholinomimetic agents, physostigmine, neostigmine, and arecoline, and the anticholinergic agents, atropine, scopolamine, and methscopolamine, have been used to explore an acetylcholine hypothesis of affect disorders and stress. Cholinomimetic drugs cause many of the same effects as do naturally occurring stressors. These include increases in negative affect, the induction of affective disorders, increases in stress neuroendocrines including ACThH, cortisol, beta‐endorphin, growth hormone, prolactin, epinephrine, and noprepinephrine, increases in blood pressure and pulse rate, and increases in analgesia. These parallel effects, combined with the effect of stress on central acetylcholine activity, suggest a stress‐acetylcholine linkage.
Biologically active phospholipids as potential cardiovascular drugs
Authors: Blankley C. John , Kaplan Harvey R. 
Published: January 2005

AbstractBoth useful and undesirable cardiovascular properties have been associated with naturally occurring and synthetically derived phospholipids. Certain phospholipids may function physiologically (or pathophysiologically) in such processes as blood pressure regulation, cardiac rhythm, and platelet aggregation. Drugs that can modify the synthesis or degradation of endogenous phospholipid mediators or selectively mimic or block their effects may be of interest as potentially useful cardiovascular agents. This article reviews the current literature in this area and defines in chemical, biochemical, and biological terms the potential of the phospholipid‐type compounds in the development of useful cardiovascular drugs.
Antagonism of bremazocine‐induced urination as a test for kappa‐opioid receptor antagonists within the phenylpiperidine series
Authors: David Leander J. , Zimmerman Dennis M. 
Published: January 2005

AbstractRepresentative compounds from a series of phenylpiperidine‐opioid antagonists were compared in their ability to antagonize the diuretic effect of 0.08 mg/kg of bremazocine, a kappa‐opioid receptor agonist. Three of the compounds produced dose‐related antagonism of bremazocine, whereas four others did not. The four ineffective compounds also did not exhibit any kappa agonist activity. The potency of the three effective antagonists did not correlated with their antagonist activity against morphine or in suppressing deprivation‐induced drinking. These results demonstrate that several kappa receptor antagonists can be found in the phenylpiperidine series of opioid antagonists, and further emphasize the usefulness of kappa‐mediated diuresis as an in vivo test for kappa‐opioid receptor activity.
Psychopathology of cognition
Authors: Hamilton Max 
Published: January 2005

AbstractDisorders of cognition can be considered in terms of perception, thought, and memory. Disorders of perception can be subdivided into sense deceptions, such as illusions and hallucinations, and sense distortions. The first are of particular interest to psychologists and physiologists. Hallucinations can occur in any of the senses, but in nonorganic conditions the most important are auditory, chiefly in the form of “voices.” The features of these are described in detail. The most important sense distortions are those of the internal senses which form the basis of the body image. Thinking covers disorders of the stream, possession, content, and form of thought. These are described in detail; and it is shown how many of the forms of thought disorder can be regarded as disturbances of association and indirectly of “set.” Disorders of memory occur most frequently in organic disease of the brain but are also found in the functional disorders. The changes seen after severe concussion serve as a model to illustrate the types of disturbance which can occur in the various aspects of the process of learning and memorizing.