Three-Dimensional Quantitative Structure−Activity Relationship Studies on Selected MT₁and MT₂Melatonin 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.

International Union of Basic and Clinical Pharmacology. LXXV. Nomenclature, Classification, and Pharmacology of G Protein-Coupled Melatonin Receptors

“…An additional pocket at the MT 2 receptor should be present and positioned out of the plane of the aromatic nucleus of melatonin, which would not be present at the MT 1 receptor. This hypothesis is supported by a threedimensional quantitative structure-activity relationship comparative molecular field analysis and statistical analysis (Rivara et al, 2003). Binding studies performed on the cloned receptors confirmed the MT 2 selectivity.…”

MT2 selective melatonin receptor antagonists: design and structure-activity relationships

“…A series of MT 1 and MT 2 antagonists, with known affinity at both receptor subtypes, was submitted to a 3D-QSAR CoMFA study to investigate their structure-activity relationships. 17 We found that MT 2 binding affinity could be enhanced by occupying the out-ofplane region surrounding positions 1 and 2 of melatonin and the region corresponding to the methoxy substituent of melatonin ( Figure 3, left); these regions proved also to be highly correlated with the selectivity for the MT 2 receptor (Figure 3, center). Another CoMFA analysis was performed on a series of melatonin receptor ligands characterized by a gradual change in their intrinsic activities, shifting from agonist to partial agonist to antagonist behavior depending on the presence or the absence of certain structural features.…”

Towards the Development of Mixed MT1‐Agonist/MT2‐Antagonist Melatonin Receptor Ligands

“…In fact, it has been previously reported that variations in size and shape of the substituent at the indole nitrogen atom of MLT analogues can modulate binding affinity and intrinsic activity toward the two MT 1 /MT 2 receptor subtypes. [40] However, indole N1 benzylation of 5-HEAT was found to be detrimental to both MT 1 and MT 2 receptor affinity (7 vs.…”