3-DIMENSIONAL QUANTITATIVE STRUCTURE-ACTIVITY RELATIONSHIP OF MELATONIN RECEPTOR LIGANDS - A COMPARATIVE MOLECULAR-FIELD ANALYSIS STUDY

A three-dimensional quantitative structure-activity relationship using the comparative molecular field analysis (CoMFA) paradigm applied to 57 melatonin receptor ligands belonging to diverse structural families was performed. The compounds studied which have been synthesized prev iously and reported to be active at chicken brain melatonin receptors were divided into a training set of 48 molecules and a test set of 9 m olecules. As most of these compounds have a highly flexible ethylamido side chain, the alignments were based on the most sterically constrai ned molecule which contains a tricyclic phenalene structure. This tric yclic compound can adopt an axial and an equatorial conformation. Two different molecular superpositions representing possible positioning w ithin the receptor site have been suggested previously. CoMFA was tent atively used to discriminate between alternate hypothetical biological ly active conformations and between possible positionings. The best 3D quantitative structure-activity relationship model found yields signi ficant cross-validated, conventional, and predictive r(2) values equal to 0.798, 0.967, and 0.76, respectively, along with an average absolu te error of prediction of 0.25 log units. These results suggest that t he active conformation of the most flexible molecules including melato nin is in a folded form if we consider the spatial position of the eth ylamido side chain relative to the aromatic ring.