DESIGN AND IN-VITRO PHARMACOLOGY OF A SELECTIVE GAMMA-AMINOBUTYRIC ACID(C) RECEPTOR ANTAGONIST

In mammals, receptors for the inhibitory neurotransmitter gamma-aminob utyric acid (GABA) are divided into three pharmacological classes, whi ch are denoted GABA(A), GABA(B), and GABA(C). GABA(C) receptors are de fined by their insensitivity to the GABA(A) receptor antagonist bicucu lline 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 recepiors are GABA-gated Cl- channels comprised of rho subunits, of which there are two subtypes. The physiological func tions served by GABA(C) receptors are largely unknown; to determine th e functions, it would be useful to have GABA(C)-selective ligands. In a previous study, we found that isoguvacine, a GABA(A)-selective agoni st, and 3-aminopropyl(methyl)phosphinic acid (3-APMPA), a GABA(B)-sele ctive agonist, show affinity for retinal GABA(C) receptors. In particu lar, 3-APMPA is an antagonist with low micromolar potency (K-b similar or equal to 1 mu M). Here, we report the synthesis and pharmacologica l characterization of (1,2,5,6-tetrahydropyridine-4-yl)methylphosphini c 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 GA BA(B) receptors. Electrical assays show that TPMPA is a competitive an tagonist of cloned human rho 1 GABA(C) receptors expressed in Xenopus laevis oocytes (K-b similar or equal to 2 mu M), TPMPA is > 100-fold w eaker as an inhibitor of rat brain GABA(A) receptors expressed in oocy tes (K-b similar or equal to 320 mu M) and has only weak agonist activ ity on GABA(B) receptors assayed in rat hippocampal slices (EC(50) sim ilar or equal to 500 mu M). TPMPA should be a useful pharmacological p robe with which to investigate GABA(C) receptor function in the outer retina and in any other areas of the nervous system in which these typ es of receptor are present.