Ajulemic acid, a synthetic nonpsychoactive cannabinoid acid, bound to the ligand binding domain of the human peroxisome proliferator-activated receptor gamma

Author(s)

Ambrosio, Andre L. B. ; Dias, Sandra M. G. ; Polikarpov, Igor ^[3] ; Zurier, Robert B. ; Burstein, Sumner H. ; Garratt, Richard C.

• Document type: Journal article
• Source: Journal of Biological Chemistry; v. 282, n. 25, p. 18625-18633, June 2007.
• Field of knowledge: Biological Sciences - Biophysics

Abstract

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 gamma of the peroxisome proliferator-activated receptor (PPAR gamma) 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 gamma isotype of human PPAR in complex with ajulemic acid, determined at 2.8-angstrom 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. (AU)

• FAPESP's process: 06/00182-8 - Structural biophysics of nuclear receptors and related proteins
• Grantee: Igor Polikarpov
• Support Opportunities: Research Projects - Thematic Grants
• FAPESP's process: 98/14138-2 - Center for Structural Molecular Biotechnology
• Grantee: Glaucius Oliva
• Support Opportunities: Research Grants - Research, Innovation and Dissemination Centers - RIDC
• FAPESP's process: 99/03387-4 - Structural studies of the proteins using synchrotron light
• Grantee: Igor Polikarpov
• Support Opportunities: Research Projects - Thematic Grants