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The three-dimensional quantitative structure−activity relationship comparative molecular field analysis (3D-QSAR CoMFA) approach was applied to some classes of melatonin (MLT) membrane receptor ligands, with the principal aim of exploring the correlation between their steric features and MT₂-selective antagonism. Binding data obtained from cloned MT₁ and MT₂ receptor subtypes were used to develop 3D-QSAR models for agonists and for antagonists at the two receptor subtypes, looking for the structural requirements for receptor subtype selectivity. In particular, we superposed the compounds showing antagonist activity, or very low intrinsic activity at the GTPγS test, following the hypothesis that the occupation of an additional pocket positioned out of the plane of MLT is one of the major determinants for MT₂ selectivity; the statistical models obtained confirmed this hypothesis. Structure−intrinsic activity …