title: Three-dimensional quantitative structure-activity relationship studies on selected MT1 and MT2 melatonin receptor ligands: requirements for subtype selectivity and intrinsic activity modulation.
abstract: 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 MT(2)-selective antagonism. Binding data obtained from cloned MT(1) and MT(2) 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 GTPgammaS 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 MT(2) selectivity; the statistical models obtained confirmed this hypothesis. Structure-intrinsic activity relationship studies, applied to a set of compounds homogeneously tested, allowed the identification of the structural features whose modulation shifts the behavior from that of the agonist to that of the antagonist. The pocket out of the plane of MLT was identified as one of the key features for obtaining selective MT(2) antagonists. The reliability of our statistical models was further confirmed by the correct prediction of the pharmacological behavior of some N-substituted melatonin derivatives, which were prepared and tested on cloned receptor subtypes.
authors.affiliation: Dipartimento Farmaceutico, Università degli Studi di Parma, Parco Area delle Scienze 27/A, Italy. silvia.rivara@unipr.it
authors.forename: Silvia
authors.initials: S
authors.lastname: Rivara
authors.forename: Marco
authors.initials: M
authors.lastname: Mor
authors.forename: Claudia
authors.initials: C
authors.lastname: Silva
authors.forename: Valentina
authors.initials: V
authors.lastname: Zuliani
authors.forename: Federica
authors.initials: F
authors.lastname: Vacondio
authors.forename: Gilberto
authors.initials: G
authors.lastname: Spadoni
authors.forename: Annalida
authors.initials: A
authors.lastname: Bedini
authors.forename: Giorgio
authors.initials: G
authors.lastname: Tarzia
authors.forename: Valeria
authors.initials: V
authors.lastname: Lucini
authors.forename: Marilou
authors.initials: M
authors.lastname: Pannacci
authors.forename: Franco
authors.initials: F
authors.lastname: Fraschini
authors.forename: Pier Vincenzo
authors.initials: PV
authors.lastname: Plazzi
mesh_terms: D008024:Ligands; D008550:Melatonin / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry*; D008958:Models, Molecular; D015233:Models, Statistical; D011758:Pyrroles / Q000138:chemical synthesis / Q000737:chemistry*; D021281:Quantitative Structure-Activity Relationship; D011956:Receptors, Cell Surface / Q000819:agonists / Q000037:antagonists & inhibitors / Q000737:chemistry*; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists / Q000037:antagonists & inhibitors / Q000737:chemistry*; D044094:Receptors, Melatonin
chemical_list: D008024:Ligands; D011758:Pyrroles; D011956:Receptors, Cell Surface; D018160:Receptors, Cytoplasmic and Nuclear; D044094:Receptors, Melatonin; D008550:Melatonin