title: N6-substituted adenosine receptor agonists. Synthesis and pharmacological activity as potent antinociceptive agents.
abstract: Novel N6-(indol-3-yl)alkyl derivatives of adenosine were synthesized. The adenosine receptor affinity and the antinociceptive activity of these compounds were assessed in binding studies and the phenylbenzoquinone-induced writhing test. Most of these analogues exhibited a potent analgesic activity without side effects. Among them, compound 3c (UP 202-32) bound to A1 (Ki = 110 nM) and A2 (Ki = 350 nM) adenosine receptors in a specific manner since it did not interact with many other receptors, especially opioid binding sites. The antinociceptive activity in the phenylbenzoquinone assay (ED50 = 3.3 mg/kg po) was antagonized by 8-cyclopentyltheophylline, suggesting that an adenosinergic mechanism underlies the analgesic activity observed with this compound. The data obtained with these new N6-substituted adenosine receptor agonists emphasize the interest of such compounds in the treatment of pain.
authors.affiliation: Carpibem, Rueil Malmaison, France.
authors.forename: T
authors.initials: T
authors.lastname: Güngör
authors.forename: P
authors.initials: P
authors.lastname: Malabre
authors.forename: J M
authors.initials: JM
authors.lastname: Teulon
authors.forename: F
authors.initials: F
authors.lastname: Camborde
authors.forename: J
authors.initials: J
authors.lastname: Meignen
authors.forename: F
authors.initials: F
authors.lastname: Hertz
authors.forename: A
authors.initials: A
authors.lastname: Virone-Oddos
authors.forename: F
authors.initials: F
authors.lastname: Caussade
authors.forename: A
authors.initials: A
authors.lastname: Cloarec
mesh_terms: D000241:Adenosine / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors / Q000138:chemical synthesis / Q000378:metabolism; D000698:Analgesia; D000700:Analgesics / Q000138:chemical synthesis* / Q000378:metabolism; D000818:Animals; D007211:Indoles / Q000037:antagonists & inhibitors / Q000138:chemical synthesis* / Q000378:metabolism; D008745:Methylation; D051379:Mice; D015394:Molecular Structure; D009584:Nitrogen / Q000737:chemistry; D058906:Purinergic P1 Receptor Agonists; D051381:Rats; D018047:Receptors, Purinergic P1 / Q000378:metabolism; D013329:Structure-Activity Relationship; D013806:Theophylline / Q000031:analogs & derivatives / Q000494:pharmacology
chemical_list: D000700:Analgesics; D007211:Indoles; D058906:Purinergic P1 Receptor Agonists; D018047:Receptors, Purinergic P1; C090929:UP 202-32; C053907:8-cyclopentyl-1,3-dimethylxanthine; D013806:Theophylline; D000241:Adenosine; D009584:Nitrogen