title: 1,3-dialkyl-8-N-substituted benzyloxycarbonylamino-9-deazaxanthines as potent adenosine receptor ligands: Design, synthesis, structure-affinity and structure-selectivity relationships.
abstract: A number of 1,3-dialkyl-9-deazaxanthines (9-dAXs), bearing a variety of N-substituted benzyloxycarbonylamino substituents at position 8, were prepared and evaluated for their binding affinity to the recombinant human adenosine receptors (hARs), chiefly to the hA(2B) and hA(2A) AR subtypes. Several ligands endowed with excellent binding affinity to the hA(2B) receptors, but low selectivity versus hA(2A) and hA(1) were identified. Among these, 1,3-dimethyl-N-3'-thienyl carbamate 15 resulted as the most potent ligand at hA(2B) (K(i)=0.8 nM), with a low selectivity versus hA(2A) (hA(2A)/hA(2B)=12.6) and hA(1) (hA(1)/hA(2B)=12.5) and a higher selectivity versus hA(3) (hA(3)/hA(2B)=454). When tested in functional assays in vitro, compound 15 exhibited high antagonist activities and efficacies versus both the A(2A) and A(2B) receptor subtypes, with pA(2) values close to the corresponding pK(i)s. A comparative analysis of structure-affinity and structure-selectivity relationships of the similar analogues 8-N-substituted benzyloxycarbonylamino- and 8-N-substituted phenoxyacetamido-9-dAXs suggested that their binding modes at the hA(2B) and hA(2A) ARs may strongly differ. Computational studies help to clarify this striking difference arising from a simple, albeit crucial, structural change, from CH(2)OCON to OCH(2)CON, in the para-position of the 8-phenyl ring.
authors.affiliation: Departamento de Química Orgánica, Facultade de Farmacia, Universidade de Santiago de Compostela, 15782 Santiago de Compostela, Spain.
authors.forename: Franco
authors.initials: F
authors.lastname: Fernández
authors.forename: Olga
authors.initials: O
authors.lastname: Caamaño
authors.forename: M
authors.initials: M
authors.lastname: Isabel Nieto
authors.forename: Carmen
authors.initials: C
authors.lastname: López
authors.forename: Xerardo
authors.initials: X
authors.lastname: García-Mera
authors.forename: Angela
authors.initials: A
authors.lastname: Stefanachi
authors.forename: Orazio
authors.initials: O
authors.lastname: Nicolotti
authors.forename: M
authors.initials: M
authors.lastname: Isabel Loza
authors.forename: Jose
authors.initials: J
authors.lastname: Brea
authors.forename: Cristina
authors.initials: C
authors.lastname: Esteve
authors.forename: Victor
authors.initials: V
authors.lastname: Segarra
authors.forename: Bernat
authors.initials: B
authors.lastname: Vidal
authors.forename: Angelo
authors.initials: A
authors.lastname: Carotti
mesh_terms: D058916:Adenosine A1 Receptor Antagonists; D058917:Adenosine A2 Receptor Antagonists; D058918:Adenosine A3 Receptor Antagonists; D000818:Animals; D002219:Carbamates / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D002460:Cell Line; D015195:Drug Design; D006801:Humans; D008297:Male; D008956:Models, Chemical; D058915:Purinergic P1 Receptor Antagonists; D051381:Rats; D017208:Rats, Wistar; D043682:Receptor, Adenosine A1 / Q000378:metabolism; D043705:Receptor, Adenosine A2A / Q000378:metabolism; D043704:Receptor, Adenosine A2B / Q000378:metabolism; D043684:Receptor, Adenosine A3 / Q000378:metabolism; D018047:Receptors, Purinergic P1 / Q000378:metabolism; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D014970:Xanthines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology
chemical_list: D058916:Adenosine A1 Receptor Antagonists; D058917:Adenosine A2 Receptor Antagonists; D058918:Adenosine A3 Receptor Antagonists; D002219:Carbamates; D058915:Purinergic P1 Receptor Antagonists; D043682:Receptor, Adenosine A1; D043705:Receptor, Adenosine A2A; D043704:Receptor, Adenosine A2B; D043684:Receptor, Adenosine A3; D018047:Receptors, Purinergic P1; D011994:Recombinant Proteins; D014970:Xanthines