HOMOLOGY MODELING OF METABOTROPIC GLUTAMATE RECEPTORS - (MGLURS) STRUCTURAL MOTIFS AFFECTING BINDING MODES AND PHARMACOLOGICAL PROFILE OF MGLUR1 AGONISTS AND COMPETITIVE ANTAGONISTS

A three-dimensional model of the amino terminal domain (ATD) of the mG luR1 receptor subtype was constructed on the basis of the previously r eported sequence homology with bacterial periplasmic proteins. The mod el was utilized for revealing structural motifs affecting the interact ion with mGluR1 agonists and competitive antagonists. The agonist bind ing site region, identified on the basis of published site-directed mu tagenesis experiments, is located on the surface of one of the two lob es constituting the mGluR1 ATD. A number of electrostatic and hydrogen -bonding interactions can be detected between mGluR1 agonists such as L-Glu (1), Quis (2), and (1S,3R)-ACPD (4) and binding site residues. A different binding mode was proposed for mGluR1 competitive antagonist s such as 4CPG (5), 4C3HPG (6), and UPF523 (10). Interactions with bot h lobes of the ATD of mGluR1 and the lack of a specific role for the p henyl moiety of mGluR1 antagonists are important features of the propo sed antagonist binding mode. The correspondence of the molecular model ing results with the pharmacological data of mGluR1 agonists and compe titive antagonists is a confirmation of the plausibility of the model.