The human GABA(B1b) and GABA(B2) heterodimeric recombinant receptor shows low sensitivity to phaclofen and saclofen

1 The aim of this study was to characterize the pharmacological profile of the GABA(B1)/GABA(B2) heterodimeric receptor expressed in Chinese hamster o vary (CHO) cells. We have compared receptor binding affinity and functional activity for a series of agonists and antagonists. 2 The chimeric G-protein, G(qi5), was used to couple receptor activation to increases in intracellular calcium for functional studies on the Fluorimet ric Imaging Plate Reader (FLIPR), using a stable GABA(B1)/GABA(B2)/G(qi5) C HO cell line. [H-3]-CGP-54626 was used in radioligand binding studies in me mbranes prepared from the same cell line. 3 The pharmacological profile of the recombinant GABA(B1/B2) receptor was c onsistent with that of native GABAB receptors in that it was activated by G ABA and baclofen and inhibited by CGP-54626A and SCH 50911. 4 Unlike native receptors, the GABA(B1)/GABA(B2)/G(qi5) response was not in hibited by high microMolar concentration of phaclofen, saclofen or CGP 3534 8. 5 This raises the possibility that the GABA(B1)/GABA(B2)/G(qi5) recombinant receptor may represent the previously described GABAB receptor subtype whi ch is relatively resistant to inhibition by phaclofen.