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_2BReceptor

Q1 · MEDICINE

Article

Author: Tanaka, Isao ; Murakami, Manabu ; Kobayashi, Seiichi ; Matsukura, Masayuki ; Nagaoka, Junsaku ; Asano, Osamu ; Horizoe, Tatsuo ; Kotake, Yoshihiko ; Niijima, Jun ; Yasuda, Nobuyuki ; Watanabe, Nobuhisa ; Minami, Hiroe ; Inoue, Takashi ; Kawata, Tsutomu ; Nagata, Kaya ; Harada, Hitoshi ; Hoshino, Yorihisa ; Yoshikawa, Seiji ; Kabasawa, Yasuhiro ; Abe, Shinya

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 2-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 (IC(50) = 0.42 microM), antagonized NECA-induced stimulation of cyclic AMP production (IC(50) = 0.063 microM). 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 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 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.

01 Mar 2000·Naunyn-Schmiedeberg's Archives of PharmacologyQ4 · MEDICINE

Activation of the A3 adenosine receptor affects cell cycle progression and cell growth

Q4 · MEDICINE

Article

Author: Brambilla, Roberta ; Kim, Yong-Chul ; Abbracchio, Maria P. ; Franceschi, Claudio ; Ceruti, Stefania ; Cattabeni, Flaminio ; Klotz, Karl-Norbert ; Lohse, Martin J. ; Jacobson, Kenneth A. ; Barbieri, Daniela

The A3 adenosine receptor has been implicated in modulation of cell growth. As a first step to the characterization of the underlying mechanisms, we exposed Chinese hamster ovary (CHO) cells transfected with the human A3 receptor (A3R-CHO) to selective A3 receptor ligands. At micromolar concentrations, the A3 agonists N6-(3-iodobenzyl)-adenosine-5'-N-methyluronamide (IB-MECA) and its 2-chloro derivative Cl-IB-MECA reduced cell number, with no effects on either parental CHO cells (not expressing any adenosine receptor), or CHO cells transfected with the human A1 receptor. Cl-IB-MECA also reduced cell number in the human HEK293 cell line transfected with the human A3 receptor cDNA as opposed to the respective untransfected wild-type cells. In A3R-CHO, agonist-induced effects were antagonized by nanomolar concentrations of A3 antagonists, including the triazoloquinazoline derivative MRS 1220, the dihydropyridine derivative MRS 1191, and the triazolonaphthyridine derivative L-249,313. A3 agonist-induced effects were not due to modulation of cell adhesion, nor to necrosis or apoptosis. Growth curves revealed highly impeded growth, and flow-cytometric analysis showed markedly reduced bromodeoxyuridine incorporation into nuclei. The effect on cell cycle was completely antagonized by MRS1191. Hence, activation of the human A3 receptor in A3R-CHO results in markedly impaired cell cycle progression, suggesting an important role for this adenosine receptor subtype in cell cycle regulation and cell growth.

01 Mar 1997·Biochemical and Biophysical Research CommunicationsQ3 · BIOLOGY

Adenosine A3Receptor Agonists Protect HL-60 and U-937 Cells from Apoptosis Induced by A3Antagonists

Q3 · BIOLOGY

Article

Author: Yao, Yao ; Sei, Yoshitatsu ; Kim, Yong-Chul ; Jiang, Ji-Long ; Abbracchio, Maria P. ; Jacobson, Kenneth A.

The effects of novel, selective adenosine (ADO) A3 receptor antagonists of diverse structure on cells of the human HL-60 leukemia and U-937 lymphoma cell lines were examined. Both 3-ethyl 5-benzyl 2-methyl-6-phenyl-4-phenylethynyl-1,4-(+/-)-dihydropyridine-3, 5-dicarboxylate (MRS 1191, 0.5 microM) and 6-carboxy-methyl-5, 9-dihydro-9-methyl-2-phenyl-[1,2,4]-triazolo [5,1-a][2,7]naphthyridine (L-249313, 0.5 microM) induced apoptotic cell death and expression of bak protein. Low concentrations of the A3 receptor agonist 2-chloro-N6-(3-iodobenzyl)adenosine-5'-N-methyluronamide (Cl-IB-MECA, 10 nM or 1 microM) protected against antagonist-induced cell death. At concentrations > or = 10 microM, the agonist alone produced apoptosis and bak expression in various cell lines. It is suggested that there exists a tonic low level of A3 receptor activation, possibly induced by release of endogenous adenosine, that results in cell protection.

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Indication	Highest Phase	Country/Location	Organization	Date
Asthma	Discovery	US	Merck & Co., Inc.	-
Inflammation	Discovery	US	Merck & Co., Inc.	-
Neoplasms	Discovery	US	Merck & Co., Inc.	-

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