jm0209580_si_001.pdf (152.59 kB)
Synthesis, Molecular Modeling Studies, and Pharmacological Activity of Selective A1 Receptor Antagonists
journal contribution
posted on 2002-09-24, 00:00 authored by Francesco Bondavalli, Maurizio Botta, Olga Bruno, Andrea Ciacci, Federico Corelli, Paola Fossa, Antonio Lucacchini, Fabrizio Manetti, Claudia Martini, Giulia Menozzi, Luisa Mosti, Angelo Ranise, Silvia Schenone, Andrea Tafi, Maria Letizia TrincavelliWe present a combined computational study aimed at identifying the three-dimensional
structural properties required for different classes of compounds to show antagonistic activity
toward the A1 adenosine receptor (AR). Particularly, an approach combining pharmacophore
mapping, molecular alignment, and pseudoreceptor generation was applied to derive a
hypothesis of the interaction pathway between a set of A1 AR antagonists taken from the
literature and a model of the putative A1 receptor. The pharmacophore model consists of seven
features and represents an improvement of the N6-C8 model, generally reported as the most
probable pharmacophore model for A1 AR agonists and antagonists. It was used to build up a
pseudoreceptor model able to rationalize the relationships between structural properties and
biological data of, and external to, the training set. In fact, to further assess its statistical
significance and predictive power, the pseudoreceptor was employed to predict the free energy
of binding associated with compounds constituting a test set. While part of these molecules
was also taken from the literature, the remaining compounds were designed and synthesized
by our research group. All of the new compounds were tested for their affinity toward A1, A2a,
and A3 AR, showing interesting antagonistic activity and A1 selectivity.