Correlation of the apparent affinities and efficacies of gamma-aminobutyric acid(C) receptor agonists

gamma -Aminobutyric acid (GABA), trans-4-aminocrotonic acid (TACA), muscimo l, imidazole-4-acetic acid (I4AA), cis-4-amino-crotonic acid (CACA), and is oguvacine are all GABA(C) receptor agonists. These compounds have different apparent sensitivities (EC50) and efficacies (I-max) on exogenously expres sed human rho1 homomeric GABA(C) receptors. It is not clear if these differ ences are due to distinct binding affinities and/or distinct gating kinetic s. In this study, using a recently developed single oocyte binding techniqu e, we determined the apparent dissociation constants (K-i values) of these compounds from their IC50 values for [H-3] GABA displacement. The apparent K-i values fell into two distinct groups. The high affinity group was compr ised of agonists with longer distances between the nitrogen atom of the ami no or imidazole group and the carbon atom of the carboxyl or isoxazole grou p. The single oocyte binding technique, in conjunction with two-electrode v oltage clamp, has allowed a direct correlation of the apparent affinity, ef ficacy, and potency of agonists on intact functional GABA(C) receptors. The correlation and coupling of these parameters are discussed in terms of a s imple proposed activation mechanism.