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Titolo:
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
Autore:
Harada, H; Asano, O; Hoshino, Y; Yoshikawa, S; Matsukura, M; Kabasawa, Y; Niijima, J; Kotake, Y; Watanabe, N; Kawata, T; Inoue, T; Horizoe, T; Yasuda, N; Minami, H; Nagata, K; Murakami, M; Nagaoka, J; Kobayashi, S; Tanaka, I; Abe, S;
Indirizzi:
Eisai & Co Ltd, Tsukuba Res Labs, Tsukuba, Ibaraki 3002635, Japan Eisai & Co Ltd Tsukuba Ibaraki Japan 3002635 kuba, Ibaraki 3002635, Japan
Titolo Testata:
JOURNAL OF MEDICINAL CHEMISTRY
fascicolo: 2, volume: 44, anno: 2001,
pagine: 170 - 179
SICI:
0022-2623(20010118)44:2<170:2ANARA>2.0.ZU;2-6
Fonte:
ISI
Lingua:
ENG
Soggetto:
DEPENDENT DIABETES-MELLITUS; MOLECULAR-CLONING; SELECTIVE AGONISTS; HUMAN BRAIN; 2-ALKYNYL DERIVATIVES; INSULIN-RESISTANCE; ZUCKER RATS; POTENT; NUCLEOSIDES; ADENOSINE-5'-N-ETHYLURONAMIDE;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
52
Recensione:
Indirizzi per estratti:
Indirizzo: Harada, H Eisai & Co Ltd, Tsukuba Res Labs, 5-1-3 Tokodai, Tsukuba, Ibaraki 3002635,Japan Eisai & Co Ltd 5-1-3 Tokodai Tsukuba Ibaraki Japan 3002635 Japan
Citazione:
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

Abstract

Novel adenosine antagonists, 2-alkynyl-8-aryl-9-methyladenine derivatives,were synthesized as candidate hypoglycemic agents. These analogues were evaluated for inhibitory activity on N-ethylcarboxamidoadenosine (NECA)-induced glucose production in primary cultured rat hepatocytes. In general, aromatic moieties at the 8-position and alkynyl groups at the 8-position had significantly increased activity compared to unsubstituted compounds. The preferred substituents at the 8-position of adenine were the 2-furyl and 3-fluorophenyl groups. In modifying the alkynyl side chain, change of the ring size, cleavage of the ring, and removal of the hydroxyl group were well tolerated. The order of the stimulatory effects of adenosine agonists on rat hepatocytes 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 production (IC50 = 0.063 muM). This inhibitory effect was much more potent than those of FK453, KF17837, and L249313 which have been reported to be respectively A(1), A(2A), and A(3) selective antagonists. These findings agree very well with the result that, compared to 15o, these selective antagonistsfor each receptor subtype showed only marginal effects in rat hepatocytes. These results suggest that adenosine agonist-induced glucose production inrat hepatocytes is mediated through the A(2B) receptor. Furthermore, 15o showed hypoglycemic activity in an animal model of noninsulin-dependent diabetes mellitus, the KK-A(y) mice. It is possible that inhibition of hepatic glucose production via the A(2B) receptor could be at least one of the mechanisms by which 15o exerts its in, vivo effects. Further elaboration of this group of compounds may afford novel antidiabetic agents.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 06/04/20 alle ore 08:01:39