title: Interaction of SSR161421, a novel specific adenosine A(3) receptor antagonist with adenosine A(3) receptor agonists both in vitro and in vivo.
abstract: A novel adenosine A(3) receptor antagonist (SSR161421) was characterized by both receptor binding assays and pharmacological tests. Binding studies on cloned human adenosine receptors showed that SSR161421 has high affinity for adenosine hA(3) receptors (K(i)=0.37 nM) with at least 1000-fold selectivity compared to hA(1), hA(2A) and hA(2B) receptors. The receptor antagonist nature of SSR161421 was determined in a functional study on Chinese hamster ovarian cells (CHO) cells expressing human adenosine A(3) receptors. SSR161421 competitively antagonized the effect of 2-chloro-N6-(3-iodobenzyl)-adenosine-5'-N-methylcarboxamide (Cl-IB-MECA) on cAMP production with a pA2 value in a luciferase reporter gene construct. In mice, intravenously administered SSR161421 inhibited the N6-(4-aminobenzyl)-adenosine-5'-N-methyl-uronamide dihydrochloride (AB-MECA) induced increase in plasma histamine levels (ED(50)=2.0mg/kg) and the Cl-IB-MECA evoked plasma extravasation (ID(50)=2.9 mg/kg) and oedema formation (ID(50)=4.6 mg/kg) in mouse ear.
authors.affiliation: Sanofi Co. Ltd., H-1045 Budapest Tó utca 1-5, Hungary. endre.mikus@labmagister.com
authors.forename: Endre G
authors.initials: EG
authors.lastname: Mikus
authors.forename: Kinga
authors.initials: K
authors.lastname: Boér
authors.forename: Géza
authors.initials: G
authors.lastname: Timári
authors.forename: Katalin
authors.initials: K
authors.lastname: Urbán-Szabó
authors.forename: Zoltán
authors.initials: Z
authors.lastname: Kapui
authors.forename: Judit
authors.initials: J
authors.lastname: Szeredi
authors.forename: Katalin
authors.initials: K
authors.lastname: Gerber
authors.forename: Tibor
authors.initials: T
authors.lastname: Szabó
authors.forename: Sándor
authors.initials: S
authors.lastname: Bátori
authors.forename: Michel
authors.initials: M
authors.lastname: Finet
authors.forename: Péter
authors.initials: P
authors.lastname: Arányi
authors.forename: Anne-Marie
authors.initials: AM
authors.lastname: Galzin
mesh_terms: D000241:Adenosine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D058909:Adenosine A3 Receptor Agonists / Q000494:pharmacology*; D058918:Adenosine A3 Receptor Antagonists / Q000008:administration & dosage / Q000494:pharmacology*; D000634:Aminoquinolines / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D001549:Benzamides / Q000008:administration & dosage / Q000494:pharmacology*; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D000242:Cyclic AMP / Q000378:metabolism; D004195:Disease Models, Animal; D004347:Drug Interactions; D004487:Edema / Q000188:drug therapy* / Q000473:pathology; D006632:Histamine / Q000097:blood; D006801:Humans; D020128:Inhibitory Concentration 50; D008297:Male; D051379:Mice; D010949:Plasma / Q000378:metabolism; D018047:Receptors, Purinergic P1 / Q000187:drug effects / Q000378:metabolism
chemical_list: C583157:4-methoxy-N-(4-benzylamino-3-cyanoquinolin-2-yl)benzamide; D058909:Adenosine A3 Receptor Agonists; D058918:Adenosine A3 Receptor Antagonists; D000634:Aminoquinolines; D001549:Benzamides; D018047:Receptors, Purinergic P1; D006632:Histamine; C089722:N(6)-(4-amino-3-iodobenzyl)adenosine-5'-N-methyluronamide; D000242:Cyclic AMP; D000241:Adenosine; C090034:2-chloro-N(6)-(3-iodobenzyl)adenosine-5'-N-methyluronamide