Details

Autor(en) / Beteiligte

• Rivara, Silvia
• Mor, Marco
• Silva, Claudia
• Zuliani, Valentina
• Vacondio, Federica
• Spadoni, Gilberto
• Bedini, Annalida
• Tarzia, Giorgio
• Lucini, Valeria
• Pannacci, Marilou
• Fraschini, Franco
• Plazzi, Pier Vincenzo

Titel

Three-Dimensional Quantitative Structure−Activity Relationship Studies on Selected MT1 and MT2 Melatonin Receptor Ligands:  Requirements for Subtype Selectivity and Intrinsic Activity Modulation

Ist Teil von

• Journal of medicinal chemistry, 2003-04, Vol.46 (8), p.1429-1439

Ort / Verlag

Washington, DC: American Chemical Society

Erscheinungsjahr

2003

Link zum Volltext

Quelle

MEDLINE

Beschreibungen/Notizen

• 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 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 MT2 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.