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J. Biol. Chem., Vol. 282, Issue 25, 18028-18036, June 22, 2007

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Nicotinic Acid Receptor Agonists Differentially Activate Downstream Effectors^*

Jeremy G. Richman¹, Martha Kanemitsu-Parks, Ibragim Gaidarov, Jill S. Cameron, Peter Griffin, Hong Zheng, Nuvia C. Guerra, Linda Cham, Dominique Maciejewski-Lenoir, Dominic P. Behan, Doug Boatman, Ruoping Chen, Philip Skinner, Pricilla Ornelas, M. Gerard Waters, Samuel D. Wright, Graeme Semple, and Daniel T. Connolly

From the Arena Pharmaceuticals, Inc., San Diego, California 92121 and the Division of Cardiovascular Diseases, Merck Research Laboratories, Rahway, New Jersey 07065

Nicotinic acid remains the most effective therapeutic agent for the treatment and prevention of atherosclerosis resulting from low high density lipoprotein cholesterol. The therapeutic actions of nicotinic acid are mediated by GPR109A, a G_i protein-coupled receptor, expressed primarily on adipocytes, Langerhans cells, and macrophage. Unfortunately, a severe, cutaneous flushing side effect limits its use and patient compliance. The mechanism of high density lipoprotein elevation is not clearly established but assumed to be influenced by an inhibition of lipolysis in the adipose. The flushing side effect appears to be mediated by the release of prostaglandin D2 from Langerhans cells in the skin. We hypothesized that the signal transduction pathways mediating the anti-lipolytic and prostaglandin D2/flushing pathways are distinct and that agonists may be identified that are capable of selectively eliciting the therapeutic, anti-lipolytic pathway while avoiding the activation of the parallel flush-inducing pathway. We have identified a number of GPR109A pyrazole agonists that are capable of fully inhibiting lipolysis in vitro and in vivo and not only fail to elicit a flushing response but can antagonize the ability of nicotinic acid to elicit a flush response in vivo. In contrast to flushing agonists, exposure of cells expressing GPR109A to the non-flushing agonists fails to induce internalization of the receptor or to activate ERK 1/2 mitogen-activated protein kinase phosphorylation.

Received for publication, March 2, 2007 , and in revised form, April 20, 2007.

^* The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Arena Pharmaceuticals, Inc., 6166 Nancy Ridge Dr., San Diego, CA 92121. Tel.: 858-453-7200; Fax: 858-812-0520; E-mail: jrichman{at}arenapharm.com.

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