2-n-Butyl-9-methyl-8-[1,2,3]triazol-2-yl-9H-purin-6-ylamine and analogues as A2A adenosine receptor antagonists. Design, synthesis, and pharmacological characterization.
Two types of adenosine receptor ligands were designed, i.e., 9H-purine and 1H-imidazo[4,5-c]pyridines, to obtain selective A(2A) antagonists, and we report here their synthesis and binding affinities for the four adenosine receptor subtypes A(1), A(2A), A(2B) and A(3). The design was carried out on the basis of the molecular modeling of a number of potent adenosine receptor antagonists described in the literature. Three compounds (25b-d) showed an interesting affinity and selectivity for the A(2A) subtype. One of them, i.e., ST1535 (2-n-butyl-9-methyl-8-[1,2,3]triazol-2-yl-9H-purin-6-ylamine, 25b) (K(i) A(2A) = 6.6 nM, K(i) A(1)/A(2A) = 12; K(i) A(2B)/A(2A) = 58; K(i) A(3)/A(2A) > 160), was selected for in vivo study and shown to induce a dose-related increase in locomotor activity, suggestive of an A(2A) antagonist type of activity.
Minetti
Patrizia
P
Istituto di Chimica Farmaceutica, Università degli Studi di Urbino Carlo Bo, Piazza del Rinascimento 6, 61029 Urbino (PU), Italy. Patrizia.Minetti@sigma-tau.it
Tinti
Maria Ornella
MO
Carminati
Paolo
P
Castorina
Massimo
M
Di Cesare
Maria Assunta
MA
Di Serio
Stefano
S
Gallo
Grazia
G
Ghirardi
Orlando
O
Giorgi
Fabrizio
F
Giorgi
Luca
L
Piersanti
Giovanni
G
Bartoccini
Francesca
F
Tarzia
Giorgio
G
D000225:Adenine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D058917:Adenosine A2 Receptor Antagonists; D000818:Animals; D002460:Cell Line; D006224:Cricetinae; D003412:Cricetulus; D015195:Drug Design; D006801:Humans; D007093:Imidazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D008297:Male; D008958:Models, Molecular; D009043:Motor Activity / Q000187:drug effects; D011687:Purines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011869:Radioligand Assay; D051381:Rats; D011916:Rats, Inbred F344; D013329:Structure-Activity Relationship; D014230:Triazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
C506291:2-n-butyl-9-methyl-8-(1,2,3)triazol-2-yl-9H-purin-6-ylamine; D058917:Adenosine A2 Receptor Antagonists; D007093:Imidazoles; D011687:Purines; D014230:Triazoles; D000225:Adenine