title: Synthesis and biological evaluation of metabolites of 2-n-butyl-9-methyl-8-[1,2,3]triazol-2-yl-9H-purin-6-ylamine (ST1535), a potent antagonist of the A2A adenosine receptor for the treatment of Parkinson's disease.
abstract: The synthesis and preliminary in vitro evaluation of five metabolites of the A2A antagonist ST1535 (1) are reported. The metabolites, originating in vivo from enzymatic oxidation of the 2-butyl group of the parent compound, were synthesized from 6-chloro-2-iodo-9-methyl-9H-purine (2) by selective C-C bond formation via halogen/magnesium exchange reaction and/or palladium-catalyzed reactions. The metabolites behaved in vitro as antagonist ligands of cloned human A2A receptor with affinities (Ki 7.5-53 nM) comparable to that of compound 1 (Ki 10.7 nM), thus showing that the long duration of action of 1 could be in part due to its metabolites. General behavior after oral administration in mice was also analyzed.
authors.affiliation: Dipartimento di Scienze Biomolecolari, Università degli Studi di Urbino , Piazza Rinascimento 6, I-61029 Urbino (PU), Italy.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Piersanti
authors.forename: Francesca
authors.initials: F
authors.lastname: Bartoccini
authors.forename: Simone
authors.initials: S
authors.lastname: Lucarini
authors.forename: Walter
authors.initials: W
authors.lastname: Cabri
authors.forename: Maria Antonietta
authors.initials: MA
authors.lastname: Stasi
authors.forename: Teresa
authors.initials: T
authors.lastname: Riccioni
authors.forename: Franco
authors.initials: F
authors.lastname: Borsini
authors.forename: Giorgio
authors.initials: G
authors.lastname: Tarzia
authors.forename: Patrizia
authors.initials: P
authors.lastname: Minetti
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology; D058917:Adenosine A2 Receptor Antagonists / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology*; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D001667:Binding, Competitive; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D008956:Models, Chemical; D015394:Molecular Structure; D010300:Parkinson Disease / Q000378:metabolism / Q000517:prevention & control*; D011869:Radioligand Assay; D043705:Receptor, Adenosine A2A / Q000235:genetics / Q000378:metabolism*; D013997:Time Factors; D014230:Triazoles / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology*
chemical_list: C506291:2-n-butyl-9-methyl-8-(1,2,3)triazol-2-yl-9H-purin-6-ylamine; D058917:Adenosine A2 Receptor Antagonists; D043705:Receptor, Adenosine A2A; D014230:Triazoles; D000225:Adenine