Design and in vitro pharmacology of a selective γ-aminobutyric acid(C) receptor antagonist

D. Ragozzino, R. M. Woodward, Y. Murata, F. Eusebi, L. E. Overman, R. Miledi

Research output: Contribution to journalArticlepeer-review


In mammals, receptors for the inhibitory neurotransmitter γ- aminobutyric acid (GABA) are divided into three pharmacological classes, which are denoted GABA(A), GABA(B), and GABA(C). GABA(C) receptors are defined by their insensitivity to the GABA(A) receptor antagonist bicuculline and the GABA(B) receptor agonist (-)-baclofen. GABA(C) receptors probably are a heterogeneous group of proteins. The most extensively studied mammalian GABA(C) receptors are those found in neurons of the outer retina. These receptors are GABA-gated Cl- channels comprised of ρ subunits, of which there are two subtypes. The physiological functions served by GABA(C) receptors are largely unknown; to determine the functions, it would be useful to have GABA(C)-selective ligands. In a previous study, we found that isoguvacine, a GABA(A)-selective agonist, and 3-aminopropyl- (methyl)phosphinic acid (3-APMPA), a GABA(B)-selective agonist, show affinity for retinal GABA(C) receptors. In particular, 3-APMPA is an antagonist with low micromolar potency (K(b) ≃ 1 μM). Here, we report the synthesis and pharmacological characterization of (1,2,5,6-tetrahydropyridine-4- yl)methylphosphinic acid (TPMPA), a hybrid of isoguvacine and 3-APMPA designed to retain affinity for GABA(C) receptors but not to interact with GABA(A) or GABA(B) receptors. Electrical assays show that TPMPA is a competitive antagonist of cloned human ρ1 GABA(C) receptors expressed in Xenopus laevis oocytes {K(b) ≃ 2 μM). TPM PA is > 100-fold weaker as an inhibitor of rat brain GABA(A) receptors expressed in oocytes (K(b) ≃ 320 μM) and has only weak agonist activity on GABA(B) receptors assayed in rat hippocampal slices (EC50 = 500 μM). TPMPA should be a useful pharmacological probe with which to investigate GABA(C) receptor function in the outer retina and in any other areas of the nervous system in which these types of receptor are present.

Original languageEnglish
Pages (from-to)1024-1030
Number of pages7
JournalMolecular Pharmacology
Issue number4
Publication statusPublished - Oct 1996

ASJC Scopus subject areas

  • Pharmacology


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