PHARMACOLOGY OF THE INHIBITORY GLYCINE RECEPTOR - AGONIST AND ANTAGONIST ACTIONS OF AMINO-ACIDS AND PIPERIDINE CARBOXYLIC-ACID COMPOUNDS

To define structure-activity relations for ligands binding to the inhi bitory glycine receptor (GlyR), the agonistic and antagonistic propert ies of alpha- and beta-amino acids were analyzed at the recombinant hu man alpha(1) GlyR expressed in Xenopus oocytes. The agonistic activity of alpha-amino acids exhibited a marked stereoselectivity and was hig hly susceptible to substitutions at the C-alpha-atom. In contrast, alp ha-amino acid antagonism was not enantiomer dependent and was influenc ed little by C-alpha-atom substitutions. The beta-amino acids taurine, beta-aminobutyric acid (beta-ABA), and beta-aminoisobutyric acid (bet a-AIBA) are partial agonists at the GlyR. Low concentrations of these compounds competitively inhibited glycine responses, whereas higher co ncentrations elicited a significant membrane current. Nipecotic acid, which contains a trans-beta-amino acid configuration, behaved as purel y competitive GlyR antagonist. Our data are consistent with the existe nce of a common binding site for all amino acid agonists and antagonis ts, at which the functional consequences of binding depend on the part icular conformation a given ligand adopts within the binding pocket. I n the case of beta-amino acids, the trans conformation appears to medi ate antagonistic receptor binding, and the cis conformation appears to mediate agonistic receptor binding. This led us to propose that the p artial agonist activity of a given beta-amino acid is determined by th e relative mole fractions of the respective cis/trans conformers.