title: 1,2,4-Triazolo[5,1-i]purine derivatives as highly potent and selective human adenosine A(3) receptor ligands.
abstract: A series of triazolopurines showed structural similarity to human adenosine A(3) receptor antagonist, 9-chloro-2-(2-furanyl)-5-[(phenylacetyl)amino][1,2,4]triazolo[1,5-c]quinazoline (MRS 1220, 1). In this study, we found novel 1,2,4-triazolo[5,1-i]purine derivatives (2) showing human adenosine A(3) receptor affinities. The compounds were obtained in two steps from 5-amino-4-cyanoimidazole (33). The affinity was determined in radioligand binding assays for the cloned human adenosine A(1), A(2A), A(2B), and A(3) receptors. After the structure-activity relationship was analyzed, we determined that there was a mild parabolic relationship between the length of alkyl groups at the 5-position and the affinities at the A(3) receptor and positive correlation between the length of the substituents on phenyl groups at the 8-position and the affinities at the A(2A) receptor. These investigations led to potent and selective human adenosine A(3) receptor ligands. The most potent A(3) receptor ligand (5-n-butyl-8-(4-methoxyphenyl)-3H-[1,2,4]triazolo[5,1-i]purine (27, K(i) = 0.18 nM) and the most selective A(3) receptor ligand against A(1), A(2A), and A(2B) receptors, (5-n-butyl-8-(4-n-propoxyphenyl)-3H-[1,2,4]triazolo[5,1-i]purine (29, >19 600), were discovered.
authors.affiliation: Nutrition Research Institute, Otsuka Pharmaceutical Factory, Inc. Tateiwa, Muya-cho, Naruto, Tokushima 772-8601 Japan. okamurtk@otsukakj.co.jp
authors.forename: Takashi
authors.initials: T
authors.lastname: Okamura
authors.forename: Yasuhisa
authors.initials: Y
authors.lastname: Kurogi
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Nishikawa
authors.forename: Kinji
authors.initials: K
authors.lastname: Hashimoto
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Fujiwara
authors.forename: Yoshimitsu
authors.initials: Y
authors.lastname: Nagao
mesh_terms: D002460:Cell Line; D006801:Humans; D008024:Ligands; D011687:Purines / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism; D043684:Receptor, Adenosine A3; D018047:Receptors, Purinergic P1 / Q000378:metabolism*; D013329:Structure-Activity Relationship; D014230:Triazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism
chemical_list: C464668:5-n-butyl-8-(4-methoxyphenyl)-3H-(1,2,4)triazolo(5,1-i)purine; C464669:5-n-butyl-8-(4-n-propoxyphenyl)-3H-(1,2,4)triazolo(5,1-i)purine; D008024:Ligands; D011687:Purines; D043684:Receptor, Adenosine A3; D018047:Receptors, Purinergic P1; D014230:Triazoles