2-alkynyl-8-aryl-9-methyladenines as novel adenosine receptor antagonists:Their synthesis and structure-activity relationships toward hepatic glucose production induced via agonism of the A(2B) receptor

Citation
H. Harada et al., 2-alkynyl-8-aryl-9-methyladenines as novel adenosine receptor antagonists:Their synthesis and structure-activity relationships toward hepatic glucose production induced via agonism of the A(2B) receptor, J MED CHEM, 44(2), 2001, pp. 170-179
Citations number
52
Language
INGLESE
art.tipo
Article
Categorie Soggetti
Chemistry & Analysis
Journal title
JOURNAL OF MEDICINAL CHEMISTRY
ISSN journal
0022-2623 → ACNP
Volume
44
Issue
2
Year of publication
2001
Pages
170 - 179
Database
ISI
SICI code
0022-2623(20010118)44:2<170:2ANARA>2.0.ZU;2-6
Abstract
Novel adenosine antagonists, 2-alkynyl-8-aryl-9-methyladenine derivatives, were synthesized as candidate hypoglycemic agents. These analogues were eva luated for inhibitory activity on N-ethylcarboxamidoadenosine (NECA)-induce d glucose production in primary cultured rat hepatocytes. In general, aroma tic moieties at the 8-position and alkynyl groups at the 8-position had sig nificantly increased activity compared to unsubstituted compounds. The pref erred substituents at the 8-position of adenine were the 2-furyl and 3-fluo rophenyl groups. In modifying the alkynyl side chain, change of the ring si ze, cleavage of the ring, and removal of the hydroxyl group were well toler ated. The order of the stimulatory effects of adenosine agonists on rat hep atocytes was NECA > CPA > CGS21680, which is consistent with involvement of the A(2B) receptor. In Chinese hamster ovary cells stably transfected with human A(2B) receptor cDNA, one of the compounds potent in hepatocytes, 15o (IC50 = 0.42 muM), antagonized NECA-induced stimulation of cyclic AMP prod uction (IC50 = 0.063 muM). This inhibitory effect was much more potent than those of FK453, KF17837, and L249313 which have been reported to be respec tively A(1), A(2A), and A(3) selective antagonists. These findings agree ve ry well with the result that, compared to 15o, these selective antagonists for each receptor subtype showed only marginal effects in rat hepatocytes. These results suggest that adenosine agonist-induced glucose production in rat hepatocytes is mediated through the A(2B) receptor. Furthermore, 15o sh owed hypoglycemic activity in an animal model of noninsulin-dependent diabe tes mellitus, the KK-A(y) mice. It is possible that inhibition of hepatic g lucose production via the A(2B) receptor could be at least one of the mecha nisms by which 15o exerts its in, vivo effects. Further elaboration of this group of compounds may afford novel antidiabetic agents.