title: Synthesis of (E)-8-(3-chlorostyryl)caffeine analogues leading to 9-deazaxanthine derivatives as dual A(2A) antagonists/MAO-B inhibitors.
abstract: A systematic modification of the caffeinyl core and substituents of the reference compound (E)-8-(3-chlorostyryl)caffeine led to the 9-deazaxanthine derivative (E)-6-(4-chlorostyryl)-1,3,5,-trimethyl-1H-pyrrolo[3,2-d]pyrimidine-2,4-(3H,5H)-dione (17f), which acts as a dual human A(2a) antagonist/MAO-B inhibitor (K(i)(A(2A)) = 260 nM; IC(50)(MAO-B) = 200 nM; IC(50)(MAO-A) = 10 μM) and dose dependently counteracts haloperidol-induced catalepsy in mice from 30 mg/kg by the oral route. The compound is the best balanced A(2A) antagonist/MAO-B inhibitor reported to date, and it could be considered as a new lead in the field of anti-Parkinson's agents. A number of analogues of 17f were synthesized and qualitative SARs are discussed. Two analogues of 17f, namely 18b and 19a, inhibit MAO-B with IC(50) of 68 and 48 nM, respectively, being 5-7-fold more potent than the prototypical MAO-B inhibitor deprenyl (IC(50) = 334 nM).
authors.affiliation: Dipartimento di Farmacia, Università degli Studi di Parma, Viale G.P. Usberti 27 A, I-43124 Parma, Italy. silvia.rivara@unipr.it
authors.forename: Silvia
authors.initials: S
authors.lastname: Rivara
authors.forename: Giovanni
authors.initials: G
authors.lastname: Piersanti
authors.forename: Francesca
authors.initials: F
authors.lastname: Bartoccini
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Diamantini
authors.forename: Daniele
authors.initials: D
authors.lastname: Pala
authors.forename: Teresa
authors.initials: T
authors.lastname: Riccioni
authors.forename: Maria Antonietta
authors.initials: MA
authors.lastname: Stasi
authors.forename: Walter
authors.initials: W
authors.lastname: Cabri
authors.forename: Franco
authors.initials: F
authors.lastname: Borsini
authors.forename: Marco
authors.initials: M
authors.lastname: Mor
authors.forename: Giorgio
authors.initials: G
authors.lastname: Tarzia
authors.forename: Patrizia
authors.initials: P
authors.lastname: Minetti
mesh_terms: D002110:Caffeine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D057809:HEK293 Cells; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D062105:Molecular Docking Simulation; D008996:Monoamine Oxidase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D014970:Xanthines / Q000737:chemistry*
chemical_list: D008996:Monoamine Oxidase Inhibitors; D014970:Xanthines; C081320:8-(3-chlorostyryl)caffeine; D002110:Caffeine