Ajulemic acid (IP-751): Synthesis, proof of principle, toxicity studies, and clinical trials

doi:10.1208/aapsj070115

AAPS J. 2005 March; 7(1): E143–E148.

Published online 2005 June 29. doi: 10.1208/aapsj070115

PMCID: PMC2751505

Ajulemic acid (IP-751): Synthesis, proof of principle, toxicity studies, and clinical trials

Summer Burstein

Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, 364 Plantation Street, 01605 Worcester, MA

Summer Burstein, Phone: (508) 856-2850, Fax: (508) 856-2003, Email: sumner.burstein/at/umassmed.edu.

Corresponding author.

Received September 27, 2004; Accepted December 12, 2004.

This article has been cited by other articles in PMC.

Abstract

Ajulemic acid (CT-3, IP-751,1’,1’-dimethylheptyl-Δ⁸ acid) (AJA) has a cannabinoid-derived structure; however, there is no evidence that it produces psychotropic actions when given at therapeutic doses. In a variety of animal assays, AJA shows efficacy in models for pain and inflammation. Furthermore, in the rat adjuvant arthritis model, it displayed a remarkable action in preventing the destruction of inflamed joints. A phase-2 human trial with chronic, neuropathic pain patients suggested that AJA could become a useful drug for treating this condition. Its low toxicity, particularly its lack of ulcerogenicity, further suggests that it will have a highly favorable therapeutic index and may replace some of the current anti-inflammatory/analgesic medications. Studies to date indicate a unique mechanism of action for AJA that may explain its lack of adverse side effects.

Keywords: ajulemic acid, analgesia, anti-inflammatory, cannabinoid, IP-751

References

1. Burstein S. Therapeutic Potential of Ajulemic Acid (CT-3) In: Grontenhermen F, Russo E, editors. Cannabis and Cannabinoids. Binghamton, NY: Haworth Press Inc; 2002. pp. 381–388.

2. Burstein SH. Ajulemic acid (CT3): a potent analog of the acid metabolites of THC. Curr Pharm Des. 2000;6:1339–1345. doi: 10.2174/1381612003399473. [PubMed] [Cross Ref]

3. Burstein SH. The cannabinoid acids: nonpsychoactive derivatives with therapeutic potential. Pharmacol Ther. 1999;82:87–96. doi: 10.1016/S0163-7258(98)00069-2. [PubMed] [Cross Ref]

4. Burstein SH, Karst M, Schneider U, Zurier RB. Ajulemic acid: a novel cannabinoid produces analgesia without a “high” Life Sci. 2004;75:1513–1522. doi: 10.1016/j.lfs.2004.04.010. [PubMed] [Cross Ref]

5. Burstein S, Hunter SA, Latham V, Renzulli L. A major metabolite of delta 1-tetrahydrocannabinol reduces its cataleptic effect in mice. Experientia. 1987;43:402–403. doi: 10.1007/BF01940427. [PubMed] [Cross Ref]

6. Burstein S, Shoupe TS. Metabolic pathways for the transformation of delta 1-tetrahydrocannabinol in mouse hepatic microsomes. Drug Metab Dispos. 1981;9:94–96. [PubMed]

7. Burstein S, Rosenfeld J, Wittstruck T. Isolation and characterization of two major urinary metabolites of 1-tetrahydrocannabinol. Science. 1972;176:422–423. doi: 10.1126/science.176.4033.422. [PubMed] [Cross Ref]

8. Burstein SH, Kupfer D. Hydroxylation of trans-1-tetrahydrocannabinol by a hepatic microsomal monooxygenase. Chem Biol Interact. 1971;3:316–316. doi: 10.1016/0009-2797(71)90078-0. [PubMed] [Cross Ref]

9. Burstein SH, Menezes F, Williamson E, Mechoulam R. Metabolism of delta 1(6)-tetrahydro-cannabinol, an active marihuana constituent. Nature. 1970;225:87–88. doi: 10.1038/225087a0. [PubMed] [Cross Ref]

10. Perez-Reyes M. Pharmacodynamics of certain drugs of abuse. In: Barnett G, Chang CN, editors. Pharmacokinetics and Pharmacodynamics of Psychoactive Drugs. Foster City, CA: Biomedical Publishers; 1985. pp. 287–310.

11. Burstein S, Hunter SA, Latham V, Renzulli L. Prostaglandins and cannabis-XVI. Antagonism of delta 1-tetrahydrocannabinol action by its metabolites. Biochem Pharmacol. 1986;35:2553–2558. doi: 10.1016/0006-2952(86)90053-5. [PubMed] [Cross Ref]

12. Burstein SH, Hull K, Hunter SA, Latham V. Cannabinoids and pain responses: a possible role for prostaglandins. FASEB J. 1988;2:3022–3026. [PubMed]

13. Burstein SH, Audette CA, Doyle SA, Hull K, Hunter SA, Latham V. Antagonism to the actions of platelet activating factor by a non-psychoactive cannabinoid. J Pharmacol Exp Ther. 1989;251:531–535. [PubMed]

14. Doyle SA, Burstein SH, Dewey WL, Welch SP. Further studies on the antinociceptive effects of delta 6-THC-7-oic acid. Agents Actions. 1990;31:157–163. doi: 10.1007/BF02003237. [PubMed] [Cross Ref]

15. Burstein SH, Audette CA, Breuer A, et al. Synthetic nonpsychotropic cannabinoids with potent antiinflammatory, analgesic, and leukocyte antiadhesion activities. J Med Chem. 1992;35:3135–3141. doi: 10.1021/jm00095a007. [PubMed] [Cross Ref]

16. Karst M, Salim K, Burstein S, Conrad I, Hoy L, Schneider U. Analgesic effect of the synthetic cannabinoid CT-3 on chronic neuropathic pain: a randomized controlled trial. JAMA. 2003;290:1757–1762. doi: 10.1001/jama.290.13.1757. [PubMed] [Cross Ref]

17. Rhee MH, Vogel Z, Barg J, et al. Cannabinol derivatives: binding to cannabinoid receptors and inhibition of adenylylcyclase. J Med Chem. 1997;40:3228–3233. doi: 10.1021/jm970126f. [PubMed] [Cross Ref]

18. Compton DR, Rice KC, Costa BR, et al. Cannabinoid structure-activity relationships: correlation of receptor binding and in vivo activities. J Pharmacol Exp Ther. 1993;265:218–226. [PubMed]

19. Recht LD, Salmonsen R, Rosetti R, et al. Antitumor effects of ajulemic acid (CT3), a synthetic non-psychoactive cannabinoid. Biochem Pharmacol. 2001;62:755–763. doi: 10.1016/S0006-2952(01)00700-6. [PubMed] [Cross Ref]

20. Hunter SA, Burstein SH. Receptor mediation in cannabinoid stimulated arachidonic acid mobilization and anandamide synthesis. Life Sci. 1997;60:1563–1573. doi: 10.1016/S0024-3205(97)00122-7. [PubMed] [Cross Ref]

21. Stebulis JA, Burstein SH, Torres R, et al. Ajulemic Acid, an antiinflammatory nonpsychoactive cannabinoid acid, modulates activation of human synovial cells. Paper presented at: 2004 Symposium on the Cannabinoids. June 20, 2004; Paestum, Italy.

22. Zurier RB, Rossetti RG, Lane JH, Goldberg JM, Hunter SA, Burstein SH. Dimethylheptyl-THC-11-oic acid: a nonpsychoactive antiinflammatory agent with a cannabinoid template structure. Arthritis Rheum. 1998;41:163–170. doi: 10.1002/1529-0131(199801)41:1<163::AID-ART20>3.0.CO;2-9. [PubMed] [Cross Ref]

23. Dajani EZ, Larsen KR, Taylor J, et al. 1′,1′-Dimethylheptyl-delta-8-tetrahydrocannabinol-11-oic acid: a novel, orally effective cannabinoid with analgesic and anti-inflammatory properties. J Pharmacol Exp Ther. 1999;291:31–38. [PubMed]

24. Burstein SH, Friderichs E, Kogel B, Schneider J, Selve N. Analgesic effects of 1′,1′ dimethylheptyl-delta8-THC-11-oic acid (CT3) in mice. Life Sci. 1998;63:161–168. doi: 10.1016/S0024-3205(98)00256-2. [PubMed] [Cross Ref]

25. Bidinger B, Torres R, Rossetti RG, et al. Ajulemic acid, a nonpsychoactive cannabinoid acid, induces apoptosis in human T lymphocytes. Clin Immunol. 2003;108:95–102. doi: 10.1016/S1521-6616(03)00064-0. [PubMed] [Cross Ref]

26. Liu J, Li H, Burstein SH, Zurier RB, Chen JD. Activation and binding of peroxisome proliferator-activated receptor gamma by synthetic cannabinoid ajulemic acid. Mol Pharmacol. 2003;63:983–992. doi: 10.1124/mol.63.5.983. [PubMed] [Cross Ref]

27. Zurier RB, Rossetti RG, Burstein SH, Bidinger B. Suppression of human monocyte interleukin-1 beta production by ajulemic acid, a nonpsychoactive cannabinoid. Biochem Pharmacol. 2003;65:649–655. doi: 10.1016/S0006-2952(02)01604-0. [PubMed] [Cross Ref]

28. Walker JM, Owen K, Petros P, Huang SM. Antiallodynic and analgesic actions of ajulemic acid reversed by a cannabinoid antagonist. Paper presented at: Society of Neuroscientists; November 9, 2000; New Orleans, LA.

29. Sumariwalla PF, Gallily R, Tchilibon S, Fride E, Mechoulam R, Feldmann M. A novel synthetic, nonpsychoactive cannabinoid acid (HU-320) with antiinflammatory properties in murine collagen-induced arthritis. Arthritis Rheum. 2004;50:985–998. doi: 10.1002/art.20050. [PubMed] [Cross Ref]

30. Burstein SH, Zurier RB. Pain reduction and lack of psychotropic effects with ajulemic acid: comment on the article by Sumariwalla et al. Arthritis Rheum. 2004;50:4078–4080. doi: 10.1002/art.20805. [PubMed] [Cross Ref]

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