title: A novel conjugated agent between dopamine and an A2A adenosine receptor antagonist as a potential anti-Parkinson multitarget approach.
abstract: We propose a potential antiparkinsonian prodrug DP-L-A(2A)ANT (2) obtained by amidic conjugation of dopamine (1) via a succinic spacer to a new triazolo-triazine A(2A) adenosine receptor (AR) antagonist A(2A)ANT (3). The affinity of 2 and its hydrolysis products-1, 3, dopamine-linker DP-L (4) and A(2A)ANT-linker L-A(2A)ANT (5)-was evaluated for hA(1), hA(2A), hA(2B) and hA(3) ARs and rat striatum A(2A)ARs or D(2) receptors. The hydrolysis patterns of 2, 4 and 5 and the stabilities of 1 and 3 were evaluated by HPLC analysis in human whole blood and rat brain homogenates. High hA(2A) affinity was shown by compounds 2 (K(i) = 7.32 ± 0.65 nM), 3 (K(i) = 35 ± 3 nM) and 5 (K(i) = 72 ± 5 nM), whose affinity values were similar in rat striatum. These compounds were not able to change dopamine affinity for D(2) receptors but counteracted the CGS 21680-induced reduction of dopamine affinity. DP-L (4) was inactive on adenosine and dopaminergic receptors. As for stability studies, compounds 4 and 5 were not degraded in incubation media. In human blood, the prodrug 2 was hydrolyzed (half-life = 2.73 ± 0.23 h) mainly on the amidic bound coupling the A(2A)ANT (3), whereas in rat brain homogenates the prodrug 2 was hydrolyzed (half-life > eight hours) exclusively on the amidic bound coupling dopamine, allowing its controlled release and increasing its poor stability as characterized by half-life = 22.5 ± 1.5 min.
authors.affiliation: Department of Pharmaceutical Sciences, University of Ferrara, Ferrara, Italy.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Dalpiaz
authors.forename: Barbara
authors.initials: B
authors.lastname: Cacciari
authors.forename: Chiara Beatrice
authors.initials: CB
authors.lastname: Vicentini
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Bortolotti
authors.forename: Giampiero
authors.initials: G
authors.lastname: Spalluto
authors.forename: Stephanie
authors.initials: S
authors.lastname: Federico
authors.forename: Barbara
authors.initials: B
authors.lastname: Pavan
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Vincenzi
authors.forename: Pier Andrea
authors.initials: PA
authors.lastname: Borea
authors.forename: Katia
authors.initials: K
authors.lastname: Varani
mesh_terms: D058917:Adenosine A2 Receptor Antagonists / Q000737:chemistry*; D000818:Animals; D016466:CHO Cells; D002851:Chromatography, High Pressure Liquid; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism; D006224:Cricetinae; D000242:Cyclic AMP / Q000378:metabolism; D004298:Dopamine / Q000737:chemistry*; D006801:Humans; D007700:Kinetics; D020734:Parkinsonian Disorders / Q000188:drug therapy; D011355:Prodrugs / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D051381:Rats
chemical_list: D058917:Adenosine A2 Receptor Antagonists; D011355:Prodrugs; D000242:Cyclic AMP; D004298:Dopamine