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0026-895X/03/6404-994-1005$20.00
Mol Pharmacol 64:994-1005, 2003

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Ki16425, a Subtype-Selective Antagonist for EDG-Family Lysophosphatidic Acid Receptors

Hideo Ohta, Koichi Sato, Naoya Murata, Alatangaole Damirin, Enkhzol Malchinkhuu, Junko Kon, Takao Kimura, Masayuki Tobo, Yuji Yamazaki, Tomoko Watanabe, Mikio Yagi, Motoko Sato, Rika Suzuki, Hideko Murooka, Teruyuki Sakai, Tsuyoshi Nishitoba, Dong-Soon Im, Hiromi Nochi, Koichi Tamoto, Hideaki Tomura, and Fumikazu Okajima

Pharmaceutical Research Laboratory, Kirin Brewery Co., Gunma, Japan (H.O., Y.Y., T.W., M.Y., M.S., R.S., H.M., T.S., T.N.); Laboratory of Signal Transduction, Institute for Molecular and Cellular Regulation, Gunma University, Maebashi, Japan (K.S., N.M., A.D., E.M., J.K., T.K., M.T., H.T., F.O.); Laboratory of Pharmacology, College of Pharmacy, Pusan National University, Busan, Republic of Korea (D.I.); and Department of Microbiology, Faculty of Pharmaceutical Sciences, Health Sciences University of Hokkaido, Ishikari-Tobetsu, Hokkaido, Japan (H.N., K.T.)

Lysophosphatidic acid (LPA) exerts a variety of biological responses through specific receptors: three subtypes of the EDG-family receptors, LPA1, LPA2, and LPA3 (formerly known as EDG-2, EDG-4, and EDG-7, respectively), and LPA4/GPR23, structurally distinct from the EDG-family receptors, have so far been identified. In the present study, we characterized the action mechanisms of 3-(4-[4-([1-(2-chlorophenyl)ethoxy]carbonyl amino)-3-methyl-5-isoxazolyl] benzylsulfanyl) propanoic acid (Ki16425) on the EDG-family LPA receptors. Ki16425 inhibited several responses specific to LPA, depending on the cell types, without any appreciable effect on the responses to other related lipid receptor agonists, including sphingosine 1-phosphate. With the cells overexpressing LPA1, LPA2, or LPA3, we examined the selectivity and mode of inhibition by Ki16425 against the LPA-induced actions and compared them with those of dioctyl glycerol pyrophosphate (DGPP 8:0), a recently identified antagonist for LPA receptors. Ki16425 inhibited the LPA-induced response in the decreasing order of LPA1 >= LPA3 » LPA2, whereas DGPP 8:0 preferentially inhibited the LPA3-induced actions. Ki16425 inhibited LPA-induced guanosine 5'-O-(3-thio)triphosphate binding as well as LPA receptor binding to membrane fractions with a same pharmacological specificity as in intact cells. The difference in the inhibition profile of Ki16425 and DGPP 8:0 was exploited for the evaluation of receptor subtypes involved in responses to LPA in A431 cells. Finally, Ki16425 also inhibited LPA-induced long-term responses, including DNA synthesis and cell migration. In conclusion, Ki16425 selectively inhibits LPA receptor-mediated actions, especially through LPA1 and LPA3; therefore, it may be useful in evaluating the role of LPA and its receptor subtypes involved in biological actions.


Received December 16, 2002; accepted July 16, 2003

Address correspondence to: Fumikazu Okajima, Ph.D., Laboratory of Signal Transduction, Institute for Molecular and Cellular Regulation, Gunma University, 3-39-15 Showa-machi, Maebashi 371-8512, Japan. E-mail: fokajima{at}showa.gunma-u.ac.jp




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