title: Design, synthesis, and structure-activity relationships of 1-,3-,8-, and 9-substituted-9-deazaxanthines at the human A2B adenosine receptor.
abstract: Over two hundred 1-, 3-, 8-, and 9-substituted-9-deazaxanthines were prepared and evaluated for their binding affinity at the recombinant human adenosine receptors, in particular at the hA(2B) and hA(2A) subtypes. Several ligands endowed with sub-micromolar to low nanomolar binding affinity at hA(2B) receptors, good selectivity over hA(2A) and hA(3), but a relatively poor selectivity over hA(1) were obtained. Good antagonistic potencies and efficacies, with pA(2) values close to the corresponding pK(i)s, were observed in functional assays in vitro performed on a selected series of compounds. 1,3-Dimethyl-8-phenoxy-(N-p-halogenophenyl)-acetamido-9-deazaxanthine derivatives appeared as the most interesting leads, some of them showing outstanding hA(2B) affinities, high selectivity over hA(2A) and hA(3), but low selectivity over hA(1). Structure-affinity relationships suggested that the binding potency at the hA(2B) receptor was mainly modulated by the steric (lipophilic) properties of the substituents at positions 1 and 3 and by the electronic and lipophilic characteristics of the substituents at position 8. A comparison among affinity and selectivity profiles of 9-deazaxanthines with the corresponding xanthines suggested some possible differences in their binding mode.
authors.affiliation: Dipartimento Farmaco-chimico, Università di Bari, via Orabona 4, I-70125 Bari, Italy. carotti@farmchim.uniba.it
authors.forename: Angelo
authors.initials: A
authors.lastname: Carotti
authors.forename: Maria Isabel
authors.initials: MI
authors.lastname: Cadavid
authors.forename: Nuria B
authors.initials: NB
authors.lastname: Centeno
authors.forename: Cristina
authors.initials: C
authors.lastname: Esteve
authors.forename: Maria Isabel
authors.initials: MI
authors.lastname: Loza
authors.forename: Ana
authors.initials: A
authors.lastname: Martinez
authors.forename: Rosa
authors.initials: R
authors.lastname: Nieto
authors.forename: Enrique
authors.initials: E
authors.lastname: Raviña
authors.forename: Ferran
authors.initials: F
authors.lastname: Sanz
authors.forename: Victor
authors.initials: V
authors.lastname: Segarra
authors.forename: Eddy
authors.initials: E
authors.lastname: Sotelo
authors.forename: Angela
authors.initials: A
authors.lastname: Stefanachi
authors.forename: Bernat
authors.initials: B
authors.lastname: Vidal
mesh_terms: D058916:Adenosine A1 Receptor Antagonists; D058917:Adenosine A2 Receptor Antagonists; D058918:Adenosine A3 Receptor Antagonists; D000818:Animals; D001667:Binding, Competitive / Q000187:drug effects; D016466:CHO Cells; D002460:Cell Line; D006224:Cricetinae; D015195:Drug Design; D006367:HeLa Cells; D006801:Humans; D015394:Molecular Structure; D051381:Rats; D017207:Rats, Sprague-Dawley; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; 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; D014970:Xanthines