Vol. 58, Issue 6, 1375-1380, December 2000

Correlation of the Apparent Affinities and Efficacies of -Aminobutyric Acid_C Receptor Agonists

Yongchang Chang, Douglas F. Covey, and David S. Weiss

Department of Neurobiology, University of Alabama at Birmingham, Birmingham, Alabama (Y.C., D.S.W.); and Department of Molecular Biology and Pharmacology, Washington University School of Medicine, St. Louis, Missouri (D.F.C.)

-Aminobutyric acid (GABA), trans-4-aminocrotonic acid (TACA), muscimol, imidazole-4-acetic acid (I4AA), cis-4-aminocrotonic acid (CACA), and isoguvacine are all GABA_C receptor agonists. These compounds have different apparent sensitivities (EC₅₀) and efficacies (I_max) on exogenously expressed human 1 homomeric GABA_C receptors. It is not clear if these differences are due to distinct binding affinities and/or distinct gating kinetics. In this study, using a recently developed single oocyte binding technique, we determined the apparent dissociation constants (K_i values) of these compounds from their IC₅₀ values for [³H]GABA displacement. The apparent K_i values fell into two distinct groups. The high affinity group was comprised of agonists with longer distances between the nitrogen atom of the amino or imidazole group and the carbon atom of the carboxyl or isoxazole group. The single oocyte binding technique, in conjunction with two-electrode voltage clamp, has allowed a direct correlation of the apparent affinity, efficacy, and potency of agonists on intact functional GABA_C receptors. The correlation and coupling of these parameters are discussed in terms of a simple proposed activation mechanism.