Author: Burstein, S.H.

Source: Current Pharmaceutical Design, Volume 6, Number 13, 1 September 2000 , pp. 1339-1345(7)

Publisher: Bentham Science Publishers

Abstract:

The acid metabolites of THC were discovered almost 30 years ago and were later shown to posses modest analgesic and anti-inflammatory activity in a variety of models. Ajulemic acid (CT3) is a more potent analog of THC-11-oic acid in which a dimethylheptyl side chain is substituted for the pentyl side chain of the naturally occurring metabolite. It produces analgesia in the mouse hot plate, the PPQ writhing, the formalin and the tail clip assays. In the latter, it was equipotent to morphine; however, it showed a much greater duration of action. In the paw edema, subcutaneous air pouch and rat adjuvant-induced arthritis models of inflammation; it showed significant therapeutic activity at a dose of 0.2 mg/kg p.o. In the arthritis model it greatly reduced permanent damage to joints when compared to an indomethacin control as evidenced by an improved joint score over vehicle controls and by histopathological examination. In contrast to the NSAIDs, it was totally nonulcerogenic at therapeutically relevant doses. Moreover, it does not depress respiration, exhibit dependence, induce body weight loss or cause mutagenesis. It shows none of the typical actions in models of the psychotropic actions of cannabinoids suggesting that a good separation of desirable from undesirable effects was achieved. Studies on its mechanism of action are currently underway. The data thus far suggest the existence of a novel receptor for ajulemic acid with possible downstream effects on eicosanoid production, cytokine synthesis and metalloprotease activity. There is also circumstantial evidence for a putative endogenous ajulemic acid, namely, arachidonylglycine.

Keywords: Ajulemic Acid (CT3); Potent Analog; Acid Metabolites of THC; THC-11-oic acid; PPQ writhing; formalin; tail clip assays; NSAIDs; THC-11-OIC ACID; AJULEMIC ACID (CT3); THC; ANALGESIC; ANTI INFLAMMATORY EFFECTS; (TNF)alpha and interleukin(IL)-1beta; TOXICITY; RECEPTOR; Chronic Ulcerogenic Effects; Indomethacin; Corpus; Antrum; Duodenum; Jejunum; Ileum; Colon; PUTATIVE ENDOGENOUS LIGANDS; Anandamide; N-arachidonyl glycine; Arachidonylglycine amide; Cyclooxygenase; Dimethylheptyl; Interleukin; Immunoreactive prostaglandin E; Non steroidal antiinflammatory drug; Para-phenylquinone; Platelet activating factor; Prostaglandin; Tetrahydrocannabinol; tumor necrosis factor

Document Type: Review article

DOI: http://dx.doi.org/10.2174/1381612003399473

Publication date: 2000-09-01

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• Current Pharmaceutical Design publishes timely in-depth reviews covering all aspects of current research in rational drug design. Each issue is devoted to a single major therapeutic area. A Guest Editor who is an acknowledged authority in a therapeutic field has solicits for each issue comprehensive and timely reviews from leading researchers in the pharmaceutical industry and academia.
  
  Each thematic issue of Current Pharmaceutical Design covers all subject areas of major importance to modern drug design, including: medicinal chemistry, pharmacology, drug targets and disease mechanism.

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