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Stereospecific Transduction of Behavioral Effects via Diazepam-Insensitive GABAA Receptors

Stereospecific Transduction of Behavioral Effects via Diazepam-Insensitive GABAA Receptors

J B Acri, G Wong, J M Witkin

Eur J Pharmacol. 1995 May 24;278(3):213-23.

PMID: 7589157

Abstract:

Previous studies reported a positive correlation between ligand affinities at diazepam-insensitive GABAA receptors and substitution for the discriminative stimulus effects of the benzodiazepine receptor antagonist, flumazenil, in pigeons. In the present experiments, bretazenil and Ro 14-5974 (ethyl-(S)-11,12,13,13 a-tetrahydro-9-oxo-9H-imidazo[1,5-a]-pyrrolo-[2,1-c] [1,4]benzodiazepine-1-carboxylate) partially substituted for, and blocked the discriminative stimulus effects of midazolam, congruent with their actions at diazepam-sensitive GABAA receptors in vitro. In addition, bretazenil and Ro 14-5974, but not their R-enantiomers, had high affinity for diazepam-insensitive receptors and fully substituted for the discriminative stimulus effects of flumazenil. The R-enantiomers of these compounds had low affinity (Ki > 1 microM) for diazepam-sensitive and diazepam-insensitive receptors, and did not share discriminative stimulus effects with flumazenil or midazolam. Ro 19-0528 (7-chloro-3-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)-4,5-dihydro-5-met hyl-6H- imidazo[1,5-a][1,4]benzodiazepin-6-one), a structurally related compound with full agonist actions at diazepam-sensitive GABAA receptors, had high diazepam-insensitive receptor affinity (Ki = 96 nM) and partially substituted for the discriminative stimulus effects of flumazenil. These results are consistent with stereospecific mediation of the discriminative stimulus effects of flumazenil through high affinity binding to diazepam-insensitive receptors in pigeons.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP1188336	Flumazenil Related Compound C		1188-33-6	Price

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