GABA(C) RECEPTOR ANTAGONISTS DIFFERENTIATE BETWEEN HUMAN P1 AND P2 RECEPTORS EXPRESSED IN XENOPUS OOCYTES

The selective GABA, receptor antagonist, (1,2,5,6-tetrahydropyridin-4- yl)methylphosphinic acid (TPMPA), is eight times more potent against h uman recombinant rho 1 receptors than rho 2 receptors expressed in Xen opus oocytes. (3-Aminopropyl)methylphosphinic acid (CGP35024), the met hylphosphinic acid analogue of GABA, and [(E)-3-aminopropen-1-yl]methy lphosphinic acid (CGP44530), an open chain analogue of TPMPA, were fiv e and four times, respectively, more potent as antagonists of rho 1 re ceptors than as antagonists of rho 2 receptors. Isoguvacine was a weak partial agonist at both rho 1 and rho 2 receptors with intrinsic acti vities (calculated as a percentage of the maximum whole cell current p roduced by a maximum dose of GABA) of 45 and 68%, respectively, of the maximum response produced by GABA. In agreement with other workers, i t was found that imidazole-4-acetic acid was a partial agonist at both rho 1 and rho 2 receptors, showing higher intrinsic activity at p2 th an at rho 1 receptors. The pi receptor antagonist, trans-4-amino-2-met hylbut-2-enoic acid (2-MeTACA), was a partial agonist at rho 2 recepto rs with an intrinsic activity of 34%. 2-MeTACA may be useful in differ entiating between homo-oligomeric rho 1 and rho 2 receptors in native systems. These studies reveal significant differences in the antagonis t profile of human recombinant rho 1 and rho 2 GABA, receptors. (C) 19 98 Elsevier Science B.V. All rights reserved.