Xorphanol Explained

Xorphanol (INN) (developmental code name TR-5379 or TR-5379M), also known as xorphanol mesylate (USAN), is an opioid analgesic of the morphinan family that was never marketed.^{[1] [2] [3]}

Xorphanol is a mixed agonist–antagonist of opioid receptors,^{[4] [5] [6]} acting preferentially as a high-efficacy partial agonist/near-full agonist of the κ-opioid receptor (K_i = 0.4 nM; EC₅₀ = 3.3 nM; = 49%; = 0.84)^{[7] [8] [9]} and to a lesser extent as a partial agonist of the μ-opioid receptor (K_i = 0.25 nM; IC₅₀ = 3.4 nM; = 29%) with lower relative intrinsic activity and marked antagonistic potential (including the ability to antagonize morphine-induced effects and induce opioid withdrawal in opioid-dependent individuals).^[10] The drug has also been found to act as an agonist of the δ-opioid receptor (K_i = 1.0 nM; IC₅₀ = 8 nM; = 76%).^[11]

Xorphanol produces potent analgesia, and was originally claimed to possess a minimal potential for dependence or abuse.^{[12] [13] [14]} Moreover, side effects in animal studies were relatively mild, with only sedation and nausea being prominent, although it also produced convulsions at the highest dose tested.^[15] However, human trials revealed additional side effects such as headaches and euphoria, and this was the subject of a lawsuit between the drug's inventors and the company to which they had licensed the marketing rights, which claimed that these side effects had not been revealed to them during the license negotiations.^[16] As a result of this dispute, the drug was never marketed commercially.

See also

• 6-Methylenedihydrodesoxymorphine
• Butorphanol
• Cyclorphan
• Ketorfanol
• Levallorphan
• Levomethorphan
• Levorphanol
• Nalmefene
• Nalbuphine
• Nalorphine
• Oxilorphan
• Proxorphan

Notes and References

1. Book: Morton IK, Hall JM . Concise Dictionary of Pharmacological Agents: Properties and Synonyms. 31 October 1999. Springer Science & Business Media. 978-0-7514-0499-9. 294–.
2. Evans SM, Lenz GR, Lessor RA . Analgesics . Annual Reports in Medicinal Chemistry . January 1990 . 25 . 11–20 (12) . Academic Press . 978-0-08-058369-3 .
3. Book: Lednicer, Daniel . vanc . The Organic Chemistry of Drug Synthesis. 25 June 1990. Wiley. 978-0-471-85548-4. 61.
4. Book: Colbern DL, Gispen WH . Neural Mechanisms and Biological Significance of Grooming Behavior. 1 January 1988. New York Academy of Sciences. 978-0-89766-441-7.
5. Gmerek DE, Cowan A . Role of opioid receptors in bombesin-induced grooming . Annals of the New York Academy of Sciences . 525 . 1 Neural Mechan . 291–300 . 1988 . 2839069 . 10.1111/j.1749-6632.1988.tb38614.x . 1988NYASA.525..291G . 2027.42/73648 . 31977725 . free .
6. Cowan A, Zhu XZ, Mosberg HI, Porreca F . Central infusion of rats with agents selective for different types of opioid receptor . NIDA Research Monograph . 67 . 132–7 . 1986 . 3018570 .
7. Gharagozlou P, Hashemi E, DeLorey TM, Clark JD, Lameh J . Pharmacological profiles of opioid ligands at kappa opioid receptors . BMC Pharmacology . 6 . 1 . 3 . January 2006 . 16433932 . 1403760 . 10.1186/1471-2210-6-3 . free .
8. Book: Bernard Testa. Advances in Drug Research. 22 October 2013. Elsevier. 978-1-4832-8798-0. 245–.
9. Gharagozlou P, Demirci H, David Clark J, Lameh J . Activity of opioid ligands in cells expressing cloned mu opioid receptors . BMC Pharmacology . 3 . 1 . January 2003 . 12513698 . 140036 . 10.1186/1471-2210-3-1 . free .
10. Book: Dr. S. S. Kadam. PRINCIPLES OF MEDICINAL CHEMISTRY Vol. - II. 1 July 2007. Pragati Books Pvt. Ltd.. 978-81-85790-03-9. 214–.
11. Gharagozlou P, Demirci H, Clark JD, Lameh J . Activation profiles of opioid ligands in HEK cells expressing delta opioid receptors . BMC Neuroscience . 3 . 1 . 19 . November 2002 . 12437765 . 137588 . 10.1186/1471-2202-3-19 . free .
12. Polazzi JO, Kotick MP, Howes JF, Bousquet AR . Analgesic narcotic antagonists. 9. 6-Methylene-8 beta-alkyl-N-(cycloalkylmethyl)-3-hydroxy- or -methoxymorphinans . Journal of Medicinal Chemistry . 24 . 12 . 1516–8 . December 1981 . 6796691 . 10.1021/jm00144a029 .
13. McCarthy PS, Howlett GJ . Physical dependence induced by opiate partial agonists in the rat . Neuropeptides . 5 . 1–3 . 11–4 . December 1984 . 6152317 . 10.1016/0143-4179(84)90014-3 . 31842402 .
14. Howes JF, Villarreal JE, Harris LS, Essigmann EM, Cowan A . Xorphanol . Drug and Alcohol Dependence . 14 . 3–4 . 373–80 . February 1985 . 4039650 . 10.1016/0376-8716(85)90068-7 .
15. Porter MC, Hartnagel RE, Clemens GR, Kowalski RL, Bare JJ, Halliwell WE, Kitchen DN . Preclinical toxicity and teratogenicity studies with the narcotic antagonist analgesic drug TR5379M . Fundamental and Applied Toxicology . 3 . 5 . 478–82 . 1983 . 6642105 . 10.1016/S0272-0590(83)80023-2 .
16. http://bulk.resource.org/courts.gov/c/F3/13/13.F3d.6.93-1385.html Maruho Company Ltd v Miles Inc (1993) 13 F.3d 6