Animal models of Parkinson׳s disease: Effects of two adenosine A2A receptor antagonists ST4206 and ST3932, metabolites of 2-n-Butyl-9-methyl-8-[1,2,3]triazol-2-yl-9H-purin-6-ylamine (ST1535).
Antagonism of the adenosine A2A receptor represents a promising strategy for non-dopaminergic treatment of Parkinson׳s disease (PD). Previously, the adenosine A2A receptor antagonist ST1535 was shown to possess potential beneficial effects in animal models of PD. Two metabolites of ST1535, namely ST3932 and ST4206, were tested in vitro to assess their affinity and activity on cloned human A2A adenosine receptors, and their metabolic profile. Additionally, ST3932 and ST4206 were investigated in vivo in animal models of PD following oral/intraperitoneal administration of 10, 20 and 40mg/kg using ST1535 as a reference compound. ST3932 and ST4206 displayed high affinity and antagonist behaviour for cloned human adenosine A2A receptors. The Ki values for ST1535, ST3932 and ST4206 were 8, 8 and 12nM, respectively, and their IC50 values on cyclic AMP were 427, 450 and 990nM, respectively. ST1535, ST3932 and ST4206 antagonized (orally) haloperidol-induced catalepsy in mice, potentiated (intraperitoneally) the number of contralateral rotations induced by l-3,4-dihydroxyphenylalanine (l-DOPA) (3mg/kg) plus benserazide (6mg/kg) in 6-Hydroxydopamine hydrobromide (6-OHDA)-lesioned rats, and increased mouse motor activity by oral route. Thus, ST3932 and ST4206, two ST1535 metabolites, show a pharmacological activity similar to ST1535, both in vitro and in vivo, and may be regarded as an interesting pharmacological alternative to ST1535.
Research & Development Area, Sigma-tau, Italy. Electronic address: mariaantonietta.stasi@sigma-tau.it.
Maria Antonietta
MA
Stasi
Research & Development Area, Sigma-tau, Italy.
Patrizia
P
Minetti
Research & Development Area, Sigma-tau, Italy.
Katia
K
Lombardo
Research & Development Area, Sigma-tau, Italy.
Teresa
T
Riccioni
Research & Development Area, Sigma-tau, Italy.
Antonio
A
Caprioli
Research & Development Area, Sigma-tau, Italy.
Mario
M
Vertechy
Research & Development Area, Sigma-tau, Italy.
Stefano
S
Di Serio
Research & Development Area, Sigma-tau, Italy.
Silvia
S
Pace
Research & Development Area, Sigma-tau, Italy.
Franco
F
Borsini
D000225:Adenine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D058917:Adenosine A2 Receptor Antagonists / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology*; D000284:Administration, Oral; D000818:Animals; D000978:Antiparkinson Agents / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology*; D001479:Basal Ganglia / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D001667:Binding, Competitive; D002375:Catalepsy / Q000139:chemically induced / Q000517:prevention & control; D000242:Cyclic AMP / Q000378:metabolism; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D057809:HEK293 Cells; D006220:Haloperidol; D006801:Humans; D007274:Injections, Intraperitoneal; D008024:Ligands; D008297:Male; D051379:Mice; D009043:Motor Activity / Q000187:drug effects*; D016627:Oxidopamine; D020734:Parkinsonian Disorders / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D011485:Protein Binding; D017207:Rats, Sprague-Dawley; D043705:Receptor, Adenosine A2A / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D014162:Transfection; D014230:Triazoles / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology*
C506291:2-n-butyl-9-methyl-8-(1,2,3)triazol-2-yl-9H-purin-6-ylamine; D058917:Adenosine A2 Receptor Antagonists; D000978:Antiparkinson Agents; D008024:Ligands; D043705:Receptor, Adenosine A2A; C000607549:ST3932; C000607548:ST4206; D014230:Triazoles; D016627:Oxidopamine; D000242:Cyclic AMP; D006220:Haloperidol; D000225:Adenine
6-OHDA model; Adenosine A(2A) receptor; Catalepsy; Motor activity; Parkinson׳s disease