GABA C receptor antagonists differentiate between human ρ1 and ρ2 receptors expressed in Xenopus oocytes

Abstract

The selective GABA C receptor antagonist, (1,2,5,6-tetrahydropyridin-4-yl)methylphosphinic acid (TPMPA), is eight times more potent against human recombinant ρ1 receptors than ρ2 receptors expressed in Xenopus oocytes. (3-Aminopropyl)methylphosphinic acid (CGP35024), the methylphosphinic acid analogue of GABA, and [( E)-3-aminopropen-1-yl]methylphosphinic acid (CGP44530), an open chain analogue of TPMPA, were five and four times, respectively, more potent as antagonists of ρ1 receptors than as antagonists of ρ2 receptors. Isoguvacine was a weak partial agonist at both ρ1 and ρ2 receptors with intrinsic activities (calculated as a percentage of the maximum whole cell current produced by a maximum dose of GABA) of 45 and 68%, respectively, of the maximum response produced by GABA. In agreement with other workers, it was found that imidazole-4-acetic acid was a partial agonist at both ρ1 and ρ2 receptors, showing higher intrinsic activity at ρ2 than at ρ1 receptors. The ρ1 receptor antagonist, trans-4-amino-2-methylbut-2-enoic acid (2-MeTACA), was a partial agonist at ρ2 receptors with an intrinsic activity of 34%. 2-MeTACA may be useful in differentiating between homo-oligomeric ρ1 and ρ2 receptors in native systems. These studies reveal significant differences in the antagonist profile of human recombinant ρ1 and ρ2 GABA C receptors.