ISSN:0272-4391    

DOI:10.1002/ddr.430040102

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

年代:1984

数据来源: WILEY

摘要:

AbstractAntagonism of selected agonist‐type drugs is an approach commonly employed to identify new drug activity. In the search for new anxiolytics, drug antagonism has not been a drug development tool in the past because of the lack of a suitable anxiogenic agonist for routine use. Recently, a number of anxiogenic drugs have been described. Pentylenetetrazol is one of those drugs. This review provides a critical examination of pentylenetetrazol with regard to its suitability as an agonist of anxiety that may be used routinely to predict and bioassay anxiolytic activity of novel molecules. In addition, drug discrimination is presented as a novel tool to measure objectively a specific animal activity which shows the same pharmacological properties as the subjectively perceived symptom of anxiety in human subjects. It is believed that the antagonism of an interoceptive discriminative stimulus produced by pentylenetetrazol may be a reliable and sensitive procedure to identify anxiolytic drugs of the futur

ISSN:0272-4391    

DOI:10.1002/ddr.430040103

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

年代:1984

数据来源: WILEY

摘要:

AbstractPharmacological and biochemical evidence supports the existence of a heterogeneous population of benzodiazepine (BDZ) receptors. One major tool which has been used to identify distinct receptor subtypes is a novel series of triazolopyridazines (TPZ) that recognize two subpopulations (types I and II) of BDZ binding sites. Earlier studies demonstrated that γ‐aminobutyric acid (GABA) enhanced specific BDZ binding and protected a fraction of BDZ binding sites against heat inactivation. GABA/BDZ interactions were further investigated by studying the properties of those BDZ binding sites that are thermostable in the presence of 1.0 mM GABA when cortical membrane fragments are heated at 60°C. Saturation isotherms of3H‐flunitrazepam (3H‐Flu) binding revealed a 90% and 60% diminution of binding sites in the absence and presence of 1 mM GABA, respectively. In the presence of 1 mM GABA, displacement of3H‐Flu binding with varied concentrations of CL 218,872, a TPZ, in heated cortical membrane preparations indicated a significant increase in the IC50value, with no effect on the Hill coefficient when compared to parallel control experiments with unheated membranes. In contrast, no significant differences in either Hill coefficients or IC50values were obtained when similar displacement experiments were performed utilizing diazepam, an agent that does not distinguish between BDZ receptor subtypes. Hofstee plots of CL 218,872 displacement of3H‐Flu binding were curvilinear in both heated and unheated membranes and could be resolved into two components by computer analysis. The relative affinity of CL 218,872 at the high‐affinity (KD1) or lowaffinity (KD2) recognition sites was unchanged after heating the membrane preparations. However, after heating, the density of type I receptors (Bmax1) was reduced 75%, while the number of type II receptors (Bmax2) was decreased only 38%. These results are indicative of a preferential GABA‐mediated protective effect on the thermal inactivation of type II BDZ re

ISSN:0272-4391    

DOI:10.1002/ddr.430040104

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

年代:1984

数据来源: WILEY

摘要:

AbstractThe endogenous ligand for the benzodiazepine receptor has not been convincingly demonstrated, nor is it clear what role this drug receptor actually plays in brain function. A number of putative endogenous ligands for the benzodiazepine receptor have been identified and reported in the literature. These putative ligands, at various stages of purification, have been typically identified by their ability to displace3H‐diazepam in a radioreceptor binding assay. Taken together, these studies provide useful information on the role that the benzodiazepine receptor and its ligand might play in brain function. The purpose of this paper is to review this area of research and attempt to provide a unifying hypothesis. In summary, calling this bioactive site the benzodiazepine receptor may be a misnomer, as it appears to effect both anxiogenic and anxiolytic activities involved in the maintenance of homeostatic levels of vigilance. Moreover, it can be suggested that endogenous ligands of reciprocal action could exist, mediating each function (relaxation and vigilance) and, thereby, maintain a balance of neural activit

ISSN:0272-4391    

DOI:10.1002/ddr.430040105

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

年代:1984

数据来源: WILEY

摘要:

AbstractHigh affinity for the brain benzodiazepine receptor can no longer be considered predictive of benzodiazepine‐like pharmacology in vivo. Studies of3H‐diazepam (3H‐DZ) and3H‐propyl‐β‐carboline‐3‐carboxylate (3H‐PrCC) binding were performed to investigate how occupation of the benzodiazepine receptor by these two high‐affinity ligands leads to their significantly different pharmacological effects. In mouse hypothalamus, there are four times as many3H‐DZ binding sites as3H‐PrCC binding sites (Bmaxvalues = 1,025 and 265 fmol/mg protein, respectively) and both types of site form a distinct anterior‐to‐posterior gradient in this tissue. Physiological Ca+2concentrations do not regulate3H‐ligand binding in Ca+2‐depleted whole mouse brain membranes, but in the presence of increasing concentrations of guanosine 5′‐triphosphate (GTP), Ca+2stimulates3H‐DZ binding up to 25%. In contrast,3H‐PrCC binding is unaffected by Ca+2and GTP. Diazepam (DZ) and ethyl β‐carboline‐3‐carboxylate (βCCE) both stimulate3H‐muscimol binding to GABA receptors in whole mouse brain membranes (DZ = +57%, βCCE = +27%), and βCCE partially blocks the effect of the benzodiazepine. Moreover, alkyl β‐carboline‐3‐carboxylates prevent a temperature‐induced thermodynamic transition in the benzodiazepine receptor that occurs in the presence of GABA. Studies of 8‐anilino‐1‐naphthalene sulfonic acid fluorescence (ANS) perturbation have also suggested that occupation of the receptor by a benzodiazepine results in a conformational change. Although benzodiazepines and β‐carbolines are high‐affinity ligands for the benzodiazepine receptor, these results suggest that their different pharmacological profiles may result f

ISSN:0272-4391    

DOI:10.1002/ddr.430040106

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

年代:1984

数据来源: WILEY

摘要:

AbstractNineteen structural analogues of γ‐aminobutyric acid (GABA) and the anxiolytics buspirone and diazepam were tested for their ability to modify GABA function in vitro. Each compound was added to the GABA receptor binding assay, the flunitrazepam receptor binding assay, the sodium‐dependent GABA binding assay, and the assay for GABA aminotransferase. It was anticipated that some of these analogues would substantially affect several of these assays. The most interesting compound to emerge was phenylthiohydantoic acid. This not only inhibited GABA receptor binding (Ki= 121 μM) but also stimulated flunitrazepam binding and inhibited the activity of GABA aminotransferase. In light of the evidence that a reduced GABA function can be a factor in anxiety, phenylthiohydantoic acid has the potential to be a GABA‐mimetic and thus be useful in the treatment of

ISSN:0272-4391    

DOI:10.1002/ddr.430040107

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

年代:1984

数据来源: WILEY

摘要:

AbstractTracazolate (ICI 136,753; 4‐butylamino‐1‐ethyl‐6‐methyl‐1H‐pyrazolo [3,4‐b] pyridine‐5‐carboxylic acid ethyl ester) exhibited dose‐related anticonflict activity in mice, rats, and squirrel monkeys. The potency of tracazolate appears to be one‐quarter to one‐half that of chlordiazepoxide, and their durations of activity are similar in rats. No tolerance to the anticonflict activity of either chlordiazepoxide or tracazolate was evident following 12 consecutive days of treatment. Tracazolate exhibits a much greater separation between sedative and therapeutic doses than does chlordiazepoxide; thus, it is predicted that tracazolate will not be sedative at anxiolytic doses in man. Furthermore, based upon studies in rodents, tracazolate should be much less likely than the benzodiazepines to potentiate the actions of barbiturates and ethanol in man. Although tracazolate is an anticonvulsant in rodents, it is considerably less potent in this respect than chlordiazepoxide. In contrast to benzodiazepine anxiolytics, tracazolate enhances the binding of3H‐benzodiazepines to their binding sites in brain. Consistent with this finding, tracazolate potentiated both the anticonvulsant and anxiolytic effects of chlordiazepoxide in rodents. Although the benzodiazepine antagonists (RO 15‐1788 and CGS 8216) clearly antagonize the anticonflict activity of chlordiazepoxide, the activity of tracazolate was not significantly altered by either antagonist. Both chlordiazepoxide and tracazolate significantly enhanced3H‐γ‐aminobutyric acid (GABA) binding. These results suggest that tracazolate is a novel psychoactive agent that should

ISSN:0272-4391    

DOI:10.1002/ddr.430040108

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

年代:1984

数据来源: WILEY

摘要:

AbstractVarious behavioral and neurochemical studies indicate that CGS 9896 may represent a novel, nonsedating anxiolytic. This substance, chemically related to the benzodiazepine antagonist CGS 8216, was effective in conflict and nonconflict models of anxiety. At the same time, CGS 9896 did not disrupt rotorod performance or decrease levels of responding in various operant procedures. In fact, CGS 9896 reversed the deficit in rotorod behavior produced by diazepam. CGS 9896 did not generalize to diazepam in rats trained to discriminate diazepam from vehicle. However, rats trained to discriminate CGS 9896 from vehicle generalized classical benzodiazepines to CGS 9896. These results suggest an anxioselective effect associated with CGS 9896 discriminative stimuli. Preliminary studies suggest that this pyrazoloquinoline does not produce dependence. Neurochemical analysis reveals that CGS 9896 binds avidly to benzodiazepine receptors both in vitro and in vivo. However, the binding characteristics of this compound differ from classical benzodiazepines in various respects. Two alternative hypotheses are discussed that may explain the behavioral and neurochemical differences between CGS 9896 and classical benzodiazepines.

ISSN:0272-4391    

DOI:10.1002/ddr.430040109

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

年代:1984

数据来源: WILEY

摘要:

AbstractA series of behavioral and neurochemical studies were performed in order to determine if buspirone (or an active metabolite of this compound) could perturb a component of the γ‐aminobutyric (GABA)‐benzodiazepine receptor‐chloride ionophore complex. In confirmation of previous findings, buspirone was shown to have anticonflict actions in both the rat and monkey. However, in these tests, buspirone was not as efficacious as benzodiazepines in producing an anticonflict action. The benzodiazepine receptor antagonists CGS 8216 and Ro 15–1788 did not reverse the anticonflict actions of buspirone. Small but statistically significant increases in the binding of [3H]diazepam to brain were observed in vivo after doses of buspirone which are active in the “thirsty rat conflict” test. However, a similar change was not observed in the ex vivo binding of [3H]flunitrazepam. These observations suggest that a metabolite of buspirone may perturb some component of the GABA‐benzodiazepine receptor‐chloride ionophore complex in an indirect fashion. Further work is necessary to determine whether a causal relationship exists between the changes in [3H]diazepam binding observed in vivo and the anticonflict acti

ISSN:0272-4391    

DOI:10.1002/ddr.430040110

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

年代:1984

数据来源: WILEY

摘要:

AbstractClinical trials have demonstrated that buspirone (BusparTM) is effective in the treatment of anxiety with efficacy and dosage comparable to diazepam or clorazepate. Buspirone is chemically distinct from the benzodiazepines as well as other psychoactive drugs. More importantly, buspirone presents a clinical pharmacologic profile which is “anxioselective”; that is, it relieves anxiety without the accompanying ancillary properties of benzodiazepines (sedation, muscle relaxation, seizure control). Biochemical investigations have not conclusively identified any direct interaction of buspirone with the benzodiazepine‐γ‐aminobutyric acid (GABA)‐chloride ionophore complex. It has been known that buspirone possesses some pharmacologic properties that are shared by dopamine antagonists. However, these properties are not characteristic solely of this class of agents. In contrast to dopamine antagonists, buspirone does not produce catalepsy. In fact, buspirone reverses catalepsy induced by dopamine antagonists. Recent investigations have demonstrated that chronic administration of dopamine antagonists increases dopamine receptor binding in experimental animals. Chronic treatment with buspirone does not have this effect. In conjunction with other observations, it has now become obvious that buspirone does not possess the postsynaptic dopamine antagonism characteristic of antipsychotic drugs. However, the mechanism by which buspirone alleviates the clinical manifestations of anxiety continues to be

ISSN:0272-4391    

DOI:10.1002/ddr.430040111

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

年代:1984

数据来源: WILEY