Synthesis, molecular modeling studies, and pharmacological activity of selective A(1) receptor antagonists.
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.
Bondavalli
Francesco
F
Dipartimento di Scienze Farmaceutiche, Università degli Studi di Genova, Viale Benedetto XV n.3, I-16132 Genova, Italy.
Botta
Maurizio
M
Bruno
Olga
O
Ciacci
Andrea
A
Corelli
Federico
F
Fossa
Paola
P
Lucacchini
Antonio
A
Manetti
Fabrizio
F
Martini
Claudia
C
Menozzi
Giulia
G
Mosti
Luisa
L
Ranise
Angelo
A
Schenone
Silvia
S
Tafi
Andrea
A
Trincavellic
Maria Letizia
ML
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
D008024:Ligands; D058915:Purinergic P1 Receptor Antagonists; D011725:Pyridines; D018047:Receptors, Purinergic P1