title: Synthesis, molecular modeling studies, and pharmacological activity of selective A(1) receptor antagonists.
abstract: We 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 A(1) 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 A(1) AR antagonists taken from the literature and a model of the putative A(1) receptor. The pharmacophore model consists of seven features and represents an improvement of the N(6)-C8 model, generally reported as the most probable pharmacophore model for A(1) 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 A(1), A(2a), and A(3) AR, showing interesting antagonistic activity and A(1) selectivity.
authors.affiliation: Dipartimento di Scienze Farmaceutiche, Università degli Studi di Genova, Viale Benedetto XV n.3, I-16132 Genova, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Bondavalli
authors.forename: Maurizio
authors.initials: M
authors.lastname: Botta
authors.forename: Olga
authors.initials: O
authors.lastname: Bruno
authors.forename: Andrea
authors.initials: A
authors.lastname: Ciacci
authors.forename: Federico
authors.initials: F
authors.lastname: Corelli
authors.forename: Paola
authors.initials: P
authors.lastname: Fossa
authors.forename: Antonio
authors.initials: A
authors.lastname: Lucacchini
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Manetti
authors.forename: Claudia
authors.initials: C
authors.lastname: Martini
authors.forename: Giulia
authors.initials: G
authors.lastname: Menozzi
authors.forename: Luisa
authors.initials: L
authors.lastname: Mosti
authors.forename: Angelo
authors.initials: A
authors.lastname: Ranise
authors.forename: Silvia
authors.initials: S
authors.lastname: Schenone
authors.forename: Andrea
authors.initials: A
authors.lastname: Tafi
authors.forename: Maria Letizia
authors.initials: ML
authors.lastname: Trincavellic
mesh_terms: D000818:Animals; D001667:Binding, Competitive; D002417:Cattle; D002540:Cerebral Cortex / Q000378:metabolism; D008024:Ligands; D008958:Models, Molecular; D058915:Purinergic P1 Receptor Antagonists; D011725:Pyridines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011869:Radioligand Assay; D018047:Receptors, Purinergic P1 / Q000737:chemistry* / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D008024:Ligands; D058915:Purinergic P1 Receptor Antagonists; D011725:Pyridines; D018047:Receptors, Purinergic P1