摘要:

AbstractGamma‐amino butyric acid (GABA) is perhaps the most abundant and important rapid inhibitory neurotransmitter in the mammalian brain. Many previous studies have indicated that GABAergic synapses are involved in drug treatments or disease processes for epilepsy, anxiety, movement disorders, depression, and psychosis. In particular, the GABAAreceptors, which rapidly open chloride ion channels and thereby clamp neuronal membrane potential to near the resting level, have received extensive study. GABABreceptors are functionally and structurally quite distinct, and there are subtypes of both GABAAand GABABreceptors. This brief review describes strategies that have been used to study GABA receptors and the pharmacology of drugs that act on GABAergic synapses. The eight reports that follow in this issue ofDrug Development Researchfocus on the pharmacology of GABAAagonists and GABA uptake inhibitors as potential therapeutic agents, and they were first presented as a satellite symposium of the 1989 meeting of the Society for Neuroscience. The following reports give special reference to Cl‐966, a novel inhibitor of GABA uptake that was developed as a potential anticonvulsant based on animal studies [Taylor et al., 1990]. Unfortunately, Cl‐966 caused severe and unexpected neurological and psychological disturbances in initial clinical studies with healthy human volunteers and has been discontinued from further development [Sedman et al., 1990]. This brief review aims to give some perspective to the following papers on GABAAagonists and GABA uptake inhib

ISSN:0272-4391    

DOI:10.1002/ddr.430210302

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1990

数据来源: WILEY

摘要:

AbstractGABA 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, GABAAand GABABreceptors. GABAAreceptors are ligand‐gated chloride channels that are sensitive to the convulsant alkaloid bicuculline and modulated by benzodiazepines and barbiturates. GABABreceptors 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 brains

ISSN:0272-4391    

DOI:10.1002/ddr.430210303

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1990

数据来源: WILEY

摘要:

AbstractMuscimol is a potent but non‐selective GABA‐A agonist. Structure‐activity studies on the (S)‐ and (R)‐forms of chiral muscimol analogues have disclosed a high degree of agonist stereoselectivity of the GABA‐A receptors. THIP (4,5,6,7‐tetrahydroisoxazolo[5,4‐c]pyridin‐3‐ol) is a specific GABA‐A agonist, which has been the subject of clinical studies in different groups of patients. Even minor alterations of the structure of THIP result in substantial or complete loss of GABA‐A agonist activity. 4‐PIOL (5‐(4‐piperidyl)isoxazol‐3‐ol) shows in vivo GABA‐A agonist activity on spinal neurones, whereas the in vitro pharmacological effects in brain tissue preparations are consistent with a GABA‐A antagonist profile of 4‐PIOL in the brain. Whereas nipetcotic acid and related GABA uptake inhibitors are substrates for the neuronal and glial transport carrier, the glia‐selective GABA uptake inhibitors THPO (4,5,6,7‐tetrahydroisoxazolo[4,5‐c]pyridin‐3‐ol) and probably also THAO (5,6,7,8‐tetrahydro‐4H‐isoxazolo[4,5‐c]azepin‐3‐ol) are not being transported by the glial uptake carrier. Introduction of the DPB (4,4‐diphenyl‐3‐butenyl) or BEE (benzhydryl ethyl ether) substituents on the basic nitrogen atoms of GABA uptake inhibitors, including nipecotic acid and THPO, results in markedly more potent inhibitors. However, unlike THPO,N‐DPB‐THPO interacts non‐selectively with neuronal and glial GABA uptake, and, in contrast to nipecotic acid,N‐DPB‐nipecotic acid (SKF‐89976‐A) has been shown not to be transported by the neuronal or glial GABA carriers. WhereasN‐DPB‐ andN‐BEE‐GABA are weak inhibitors of

ISSN:0272-4391    

DOI:10.1002/ddr.430210304

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1990

数据来源: WILEY

摘要:

AbstractA lipophilic derivative of the known GABA uptake inhibitor guvacine has been prepared. The synthesis of this compound, [1‐]2‐bis 4‐(trifluoromethyl)]phenyl[‐methoxy]ethyl[‐ 1,2,5,6‐tet‐rahydro‐3‐pyridine carboxylic acid, monohydrochloride, Cl‐966, is described. Studies were carried out to determine the metabolic profile of Cl‐966, in rats. Two metabolites, one less polar and the other more polar than Cl‐966, were identified and their structures assigned by spectroscopic methods and confirmed by compariso

ISSN:0272-4391    

DOI:10.1002/ddr.430210305

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1990

数据来源: WILEY

摘要:

AbstractExperiments were performed to assess the pharmacology of a novel inhibitor of GABA uptake, Cl‐966 ([1‐[2‐[bis 4‐(trifluoromethyl)phenyl]methoxy]ethyl]‐1,2,5,6‐tetrahydro‐3‐pyridinecarboxylic acid, HCl salt; the molecular weight of the free acid is 473.8). Cl‐966 potently inhibits tritiated GABA uptake into rat hippocampal slices in vitro (lC50= 304 nM). It has no appreciable effect on the uptake of other neurotransmitters tested (aspartate, dopamine, norepinephrine, serotonin) and has low activity in a broad range of neurotransmitter receptor binding assays. When given orally to mice, Cl‐966 prevents tonic extensor seizures from low‐intensity electroshock and prevents pentylenetetrazole‐induced clonic seizures (ED50= 0.4–1.0 mg/kg). In addition, the hippocampal afterdischarge threshold in kindled rats is increased markedly (ED50= 2.6 mg/kg p.o.). Despite anticonvulsant effects, higher doses of Cl‐966 reduce the intravenous dose of pentylenetetrazole needed to produce clonus in mice. In mice, rats, dogs, and monkeys, Cl‐966 interferes with normal behavior, causing ataxia, reduced responsivenes and myoclonus. In the hippocampus of anesthetized rats, Cl‐966 increases inhibition measured electrophysiologically. Overflow of endogenous GABA in the striatum (measured with in vivo microdialysis) was also increased. All of these observed effects with Cl‐966 may be explained by its

ISSN:0272-4391    

DOI:10.1002/ddr.430210306

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1990

数据来源: WILEY

摘要:

Abstract[1‐[2‐[bis(trifluoromethyl)‐phenyl]methoxy]ethyl]‐ 1,2,5,6‐tetrahydro‐3‐pyridine‐carboxylic acid, HCl (Cl‐966, Parke‐Davis) is a new specific inhibitor of GABA uptake to neurons that is severalfold more potent than for inhibition of glycine or glutamate uptake. Cl‐966 crosses the blood‐brain barrier and when injected intravenously into rats (doses up to 10.5 μM/Kg = 5.0 mg/kg) produces only marginal behavioral effects. Cl‐966 also produces a modest reversal of punished‐suppressed drinking behavior in thristy rats both in the conflict and phenylenetetrazole (PTZ)‐induced proconflict Vogel test. However an inactive dose of Cl‐966 (6.3 μM/kg i.v., 90 min prior to the test) significantly potentiated the anticonflict and anti‐PTC‐induced proconflict action of diazepam and alprazolam. The anticonflict/antiproconflict ED50ratio for diazepam was shifted from 1.2 to 1.0 and that of alprazolam from 13.0 to 7.0 after pretreatment with Cl‐966.These results suggest that Cl‐966, while it may produce increasing GABAergic tone throughout the CNS, selectively enhances the action of GABA at GABAAreceptor subtypes whose sensitivity is preferentially increased by administration of positive allosteric modulators. Therefore Cl‐966 may represent a very useful drug to study modifications of animal behavior in relation to the function of GAB

ISSN:0272-4391    

DOI:10.1002/ddr.430210307

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1990

数据来源: WILEY

摘要:

AbstractGABAmimetic 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 dyskinesi

ISSN:0272-4391    

DOI:10.1002/ddr.430210308

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1990

数据来源: WILEY

摘要:

AbstractAn initial double‐blind, placebo‐controlled safety and tolerance study of single doses of a GABA uptake inhibitor (CI‐966) being developed for the treatment of epilepsy was conducted in healthy volunteers. Drug doses of 1 to 10 mg were well tolerated. A volunteer who received 25 mg of CI‐966 developed transient short‐ and long‐term memory deficits. Both volunteers following administration of 50 mg drug doses presented with a constellation of physical and mental disturbances. Physical abnormalities including tremor, myoclonus, increased muscle rigidity, cogwheeling, and short‐ and long‐term memory impairment of 12–24 hr duration were observed. In addition, striking psychiatric symptoms of many days' duration resembling those seen in patients with mania and schizophrenia were evident. These findings suggest that GABA may modulate memory and dopaminergic pathways responsible for posture and muscle control. In addition, GABA may be a potentially important mediator in the pathogenesis of schizo

ISSN:0272-4391    

DOI:10.1002/ddr.430210309

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1990

数据来源: WILEY

摘要:

AbstractThis experiment determined if two novel compounds, zolpidem and CI‐966, would show anxiogenic or anxiolytic activity in an animal model of anxiety based upon the discrimination of pentylentetrazole (PTZ). Rats were trained to detect the anxiogenic drug PTZ, 20 mg/kg, and tested with zolpidem (an agonist at omega [benzodiazepine] receptors) and CI‐966 (a GABA‐uptake inhibitor). Zolpidem did not substitute for PTZ. This drug blocked the PTZ stimulus in a dose‐related manner (0.32–5.0 mg/kg), although only partial blockade was obtained even at the highest dose that could be tested. These data suggest that zolpidem may have weak efficacy as an anxiolytic drug. CI‐966 partially substituted for PTZ at 3 to 6 hr post injection of doses of 16.0 and 32.0 mg/kg. Lower doses of CI‐966 produced a slight, but non‐significant, blockade of the PTZ stimulus, which appeared to be additive with the blocking effects of diazepam upon this discrimination. Because CI‐966 has been shown to block PTZ seizures in mice, the present data suggest that the discriminative stimulus produced by PTZ is not related to its ability to produce convulsions. The partial substitution of CI‐966 given in high doses is consistent with clinical reports that this compound may produce

ISSN:0272-4391    

DOI:10.1002/ddr.430210310

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1990

数据来源: WILEY

摘要:

AbstractHallucinogenic 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 GABAAreceptor will provide clues to schizophrenia remains to be elucida

ISSN:0272-4391    

DOI:10.1002/ddr.430210311

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1990

数据来源: WILEY