AFFINITY OF VARIOUS LIGANDS FOR GABA(A) RECEPTORS CONTAINING ALPHA(4)BETA(3)GAMMA(2), ALPHA(4)GAMMA(2), OR ALPHA(1)BETA(3)GAMMA(2) SUBUNITS

The potency of 30 benzodiazepine binding site ligands from 14 differen t structural classes for inhibition of [H-3]Ro 15-4513 zido-5,6-dihydr o-5-methyl-6-oxo-4H-imidazo[1,5-a][ 1,4]benzodiazepine-3-carboxylate) binding to human embryonic kidney (HEK) 293 cells transiently transfec ted with alpha(4) beta(3) gamma(2S) or alpha(1) beta(3) gamma(2S) subu nits of GABA(A) receptors was investigated. Most of these compounds we re unable to significantly inhibit [H-3]Ro 15-4513 binding to alpha(4) beta(3) gamma(2S) receptors under conditions where they potently inhi bited binding to alpha(1) beta(3) gamma(2S) receptors. Nevertheless, c ompounds from four different structural classes were identified which exhibited a high affinity for alpha(4) beta(3) gamma(2S) receptors. Va riation of the structure of these compounds could lead to new ligands selectively interacting with alpha(4) beta(3) gamma(2S) receptors. Com pounds interacting with alpha(4) beta(3) gamma(2S) receptors were also able to inhibit [H-3]Ro 15-4513 binding to receptors consisting of al pha(4) gamma(2S) subunits with comparable potency. These results suppo rt the conclusion that the a subunit is a major determinant of the ben zodiazepine binding site properties of GABA, receptors containing a an d gamma subunits.