3-hydroxymethyl-beta-carboline and beta-carboline-3-carboxylic-acid-ethyl-ester

Rats were trained to discriminate between saline and 1.0 mg/kg of diazepam in a two-choice procedure where responding was maintained under a fixed-ratio, 5-response schedule of stimulus shock termination. beta-Carboline-3-carboxylate-methyl ester (beta CCM), beta-carboline-3-carboxylate-ethyl ester (beta CCE) and beta-carboline-3-carboxylate-t-butyl ester (beta CCtB), compounds with alkylcarboxy substitutions on the 3-position of the beta-carboline ring structure, were effective antagonists of the discriminative effects of diazepam. The 3-hydroxymethyl-substituted compound (3HMC) was relatively ineffective in antagonizing the discriminative effects of diazepam. The order of potency in antagonizing the 1.0 mg/kg training dose of diazepam was beta CCtB greater than beta CCM greater than beta CCE much greater than 3 HMC. The greater potency of beta CCtB likely reflects its resistance to metabolism in vivo. beta CCE and beta CCtB produced dose-related, parallel shifts in the dose-response curve for the discriminative effects of diazepam, but the magnitude of the shifts was limited: the two highest doses of beta CCE and beta CCtB produced shifts that were not significantly different in magnitude. These latter results suggest that these beta-carbolines antagonize only a portion of the component(s) of action of diazepam in producing discriminative stimuli. In contrast, the 7-substituted beta-carbolines harmane, harmol and harmine were ineffective in antagonizing the discriminative effects of diazepam up to doses of the beta-carbolines which disrupted the ability of the animals to respond.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Carbolines; Diazepam; Discrimination Learning; Harmine; Male; Picrotoxin; Rats; Rats, Inbred F344

The discovery of high affinity, stereoselective binding sites for benzodiazepines (BZ) was a major step in understanding the molecular mechanism by which these widely used sedative/hypnotics exert their various pharmacologic effects. It has become clear that the BZ receptor complex has functional significance in terms of the anxiolytic, anticonvulsant and muscle relaxant properties of these widely used compounds. Until recently its role in the sleep-inducing properties has been unclear. This paper reviews a series of studies indicating that the BZ receptor complex does indeed mediate the hypnotic effects of flurazepam, and that these effects may involve alterations in calcium flow across neuronal membranes. Preliminary evidence also suggests that some pharmacologic properties of barbiturates may involve interactions with portions of the benzodiazepine receptor complex. Lethality from pentobarbital in mice, for instance, can be greatly reduced by treatment with IPPO, a compound which binds in relation to the chloride ionophore. The implications of sub-types of BZ receptors are discussed. Experience with some compounds which bind at the BZ receptor suggests that in the future drugs may become available which are much more specific for individual desired effects.

Topics: Animals; Barbiturates; Benzodiazepines; Benzodiazepinones; Calcium; Carbolines; Diazepam; Flumazenil; Flurazepam; Humans; Motor Activity; Nifedipine; Phenobarbital; Pyrazoles; Rats; Receptors, GABA-A; Sleep; Synaptosomes