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J. Biol. Chem., Vol. 282, Issue 25, 18625-18633, June 22, 2007

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Ajulemic Acid, a Synthetic Nonpsychoactive Cannabinoid Acid, Bound to the Ligand Binding Domain of the Human Peroxisome Proliferator-activated Receptor ^*

Andre L. B. Ambrosio¹, Sandra M. G. Dias, Igor Polikarpov, Robert B. Zurier^¶, Sumner H. Burstein^||, and Richard C. Garratt²

From the Centro de Biotecnologia Molecular Estrutural, Instituto de Física de São Carlos, Universidade de São Paulo, São Carlos-SP CEP 13560-970, Brazil, the C3-137 Veterinary Medical Center, Cornell University, Ithaca, New York 14853, and the Departments of ^¶Medicine and ^||Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Worcester, Massachusetts 01605

Ajulemic acid (AJA) is a synthetic analog of THC-11-oic acid, a metabolite of tetrahydrocannabinol (THC), the major active ingredient of the recreational drug marijuana derived from the plant Cannabis sativa. AJA has potent analgesic and anti-inflammatory activity in vivo, but without the psychotropic action of THC. However, its precise mechanism of action remains unknown. Biochemical studies indicate that AJA binds directly and selectively to the isotype of the peroxisome proliferator-activated receptor (PPAR) suggesting that this may be a pharmacologically relevant receptor for this compound and a potential target for drug development in the treatment of pain and inflammation. Here, we report the crystal structure of the ligand binding domain of the isotype of human PPAR in complex with ajulemic acid, determined at 2.8-Å resolution. Our results show a binding mode that is compatible with other known partial agonists of PPAR, explaining their moderate activation of the receptor, as well as the structural basis for isotype selectivity, as observed previously in vitro. The structure also provides clues to the understanding of partial agonism itself, suggesting a rational approach to the design of molecules capable of activating the receptor at levels that avoid undesirable side effects.

Received for publication, March 23, 2007 , and in revised form, April 16, 2007.

The atomic coordinates and structure factors (code 2OM9) have been deposited in the Protein Data Bank, Research Collaboratory for Structural Bioinformatics, Rutgers University, New Brunswick, NJ (http://www.rcsb.org/).

^* This work was supported by São Paulo State Research Foundation Grants 03/00231-0 (to A. L. B. A.), 99/03387-4, and 06/00182-8 (to I. P.) and 98/14138-2 (Centro de Biotecnologia Molecular Estrutural), and National Institutes of Health Grants RO1 DA13691 and U19 AI056362 (to R. B. Z.). 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 Current address: C3-137 Veterinary Medical Center, Cornell University, Ithaca, NY 14853. To whom correspondence may be addressed: Tel.: 607-253-3653; Fax: 607-253-3659; E-mail: ala48{at}cornell.edu.

² To whom correspondence may be addressed. Tel.: 55-16-3373-9846; Fax: 55-16-3373-9881; E-mail: richard{at}if.sc.usp.br.

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