FULL AND PARTIAL AGONISM DISPLAYED BY BENZODIAZEPINE RECEPTOR LIGANDSAT RECOMBINANT GAMMA-AMINOBUTYRIC ACID(A) RECEPTOR SUBTYPES

The differences in intrinsic activity and receptor subtype specificity of the newly developed benzodiazepine receptor ligands bretazenil, di vaplon and abecarnil were assessed in recombinant gamma-aminobutyric a cid(A) (GABA(A)) receptors expressed in mammalian cells from the subun it-cDNA combinations alpha3beta2gamma2 and alpha5beta2gamma2. Chloride currents induced by rapid application of GABA in the presence or abse nce of drugs were measured using the whole-cell configuration of the p atch-clamp technique. Bretazenil displayed an intrinsic activity which amounted only to 58 +/- 7% and 35 +/- 11% of that of flunitrazepam at the alpha3beta2gamma2 and alpha5beta2gamma2 combination, respectively . The maximum potentiation by divaplon was only 28 +/- 5% and 21 +/- 9 % of that of flunitrazepam at the respective subunit combinations. Thu s, the partial agonism postulated for bretazenil and divaplon on pharm acological grounds is shown to be operative on the level of single GAB A(A) receptors. Most strikingly, abecarnil potentiated the GABA respon se to the same degree as flunitrazepam at the alpha3beta2gamma2 combin ation but to only 52 +/- 14% compared to flunitrazepam at the alpha5be ta2gamma2 combination. This finding demonstrates that the intrinsic ac tivity of benzodiazepine receptor ligands can vary among the receptor subtypes with the degree of receptor modulation being influenced by th e type of a subunit.