xorphanol

{{Short description|Opioid analgesic}}

{{Drugbox

| Verifiedfields = changed

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| verifiedrevid = 448118966

| IUPAC_name = N-(Cyclobutylmethyl)-8β-methyl-6-methylenemorphinan-3-ol

| image = Xorphanol.svg

| image_class = skin-invert-image

| alt = Structural formula

| width = 205

| image2 = Xorphanol molecule ball.png

| alt2 = Ball-and-stick model

| width2 = 220

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| CAS_number_Ref = {{cascite|correct|??}}

| CAS_number = 77287-89-9

| ATC_prefix = none

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| PubChem = 5488631

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| UNII = L415991P58

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| ChemSpiderID = 20121496

| C=23 | H=31 | N=1 | O=1

| smiles = C[C@H]1CC(=C)C[C@@]23[C@@H]1[C@@H](CC4=C2C=C(C=C4)O)N(CC3)CC5CCC5

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| StdInChI = 1S/C23H31NO/c1-15-10-16(2)22-21-11-18-6-7-19(25)12-20(18)23(22,13-15)8-9-24(21)14-17-4-3-5-17/h6-7,12,16-17,21-22,25H,1,3-5,8-11,13-14H2,2H3/t16-,21+,22-,23+/m0/s1

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Xorphanol (INN; also known as xorphanol mesylate (USAN); developmental codes TR-5379 or TR-5379M) is an opioid analgesic of the morphinan family that was never marketed.{{cite book| vauthors = Morton IK, Hall JM |title=Concise Dictionary of Pharmacological Agents: Properties and Synonyms|url=https://books.google.com/books?id=mqaOMOtk61IC&pg=PA294|date=31 October 1999|publisher=Springer Science & Business Media|isbn=978-0-7514-0499-9|pages=294–}}{{cite journal | vauthors = Evans SM, Lenz GR, Lessor RA | title = Analgesics | journal = Annual Reports in Medicinal Chemistry | date = January 1990 | volume = 25 | pages = 11–20 (12) | publisher = Academic Press | url= https://books.google.com/books?id=NZZbEkldeJAC&pg=PA12 |isbn=978-0-08-058369-3 }}{{cite book| first = Daniel | last = Lednicer | name-list-style = vanc |title=The Organic Chemistry of Drug Synthesis|url=https://books.google.com/books?id=1RBtAAAAMAAJ|date=25 June 1990|publisher=Wiley|isbn=978-0-471-85548-4|page=61}}

Xorphanol is a mixed agonist–antagonist of opioid receptors,{{cite book| vauthors = Colbern DL, Gispen WH |title=Neural Mechanisms and Biological Significance of Grooming Behavior|url=https://books.google.com/books?id=EVEeAQAAIAAJ|date=1 January 1988|publisher=New York Academy of Sciences|isbn=978-0-89766-441-7}}{{cite journal | vauthors = Gmerek DE, Cowan A | title = Role of opioid receptors in bombesin-induced grooming | journal = Annals of the New York Academy of Sciences | volume = 525 | issue = 1 Neural Mechan | pages = 291–300 | year = 1988 | pmid = 2839069 | doi = 10.1111/j.1749-6632.1988.tb38614.x | bibcode = 1988NYASA.525..291G | hdl = 2027.42/73648 | s2cid = 31977725 | url = https://deepblue.lib.umich.edu/bitstream/2027.42/73648/1/j.1749-6632.1988.tb38614.x.pdf | hdl-access = free }}{{cite journal | vauthors = Cowan A, Zhu XZ, Mosberg HI, Porreca F | title = Central infusion of rats with agents selective for different types of opioid receptor | journal = NIDA Research Monograph | volume = 67 | pages = 132–7 | year = 1986 | pmid = 3018570 }} 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; {{abbr|I_max|maximum inhibition}} = 49%; {{abbr|IA|relative intrinsic activity}} = 0.84){{cite journal | vauthors = Gharagozlou P, Hashemi E, DeLorey TM, Clark JD, Lameh J | title = Pharmacological profiles of opioid ligands at kappa opioid receptors | journal = BMC Pharmacology | volume = 6 | issue = 1 | pages = 3 | date = January 2006 | pmid = 16433932 | pmc = 1403760 | doi = 10.1186/1471-2210-6-3 | doi-access = free }}{{cite book|author=Bernard Testa|title=Advances in Drug Research|url=https://books.google.com/books?id=eiAlBQAAQBAJ&pg=PA245|date=22 October 2013|publisher=Elsevier|isbn=978-1-4832-8798-0|pages=245–}}{{cite journal | vauthors = Gharagozlou P, Demirci H, David Clark J, Lameh J | title = Activity of opioid ligands in cells expressing cloned mu opioid receptors | journal = BMC Pharmacology | volume = 3 | pages = 1 | date = January 2003 | pmid = 12513698 | pmc = 140036 | doi = 10.1186/1471-2210-3-1 | doi-access = free }} and to a lesser extent as a partial agonist of the μ-opioid receptor (K_i = 0.25 nM; IC₅₀ = 3.4 nM; {{abbr|I_max|maximum inhibition}} = 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).{{cite book|author=Dr. S. S. Kadam|title=PRINCIPLES OF MEDICINAL CHEMISTRY Vol. - II|url=https://books.google.com/books?id=Z7Pb3lJuRksC&pg=PA214|date=1 July 2007|publisher=Pragati Books Pvt. Ltd.|isbn=978-81-85790-03-9|pages=214–}} The drug has also been found to act as an agonist of the δ-opioid receptor (K_i = 1.0 nM; IC₅₀ = 8 nM; {{abbr|I_max|maximum inhibition}} = 76%).{{cite journal | vauthors = Gharagozlou P, Demirci H, Clark JD, Lameh J | title = Activation profiles of opioid ligands in HEK cells expressing delta opioid receptors | journal = BMC Neuroscience | volume = 3 | issue = 1 | pages = 19 | date = November 2002 | pmid = 12437765 | pmc = 137588 | doi = 10.1186/1471-2202-3-19 | doi-access = free }}

Xorphanol produces potent analgesia, and was originally claimed to possess a minimal potential for dependence or abuse.{{cite journal | vauthors = Polazzi JO, Kotick MP, Howes JF, Bousquet AR | title = Analgesic narcotic antagonists. 9. 6-Methylene-8 beta-alkyl-N-(cycloalkylmethyl)-3-hydroxy- or -methoxymorphinans | journal = Journal of Medicinal Chemistry | volume = 24 | issue = 12 | pages = 1516–8 | date = December 1981 | pmid = 6796691 | doi = 10.1021/jm00144a029 }}{{cite journal | vauthors = McCarthy PS, Howlett GJ | title = Physical dependence induced by opiate partial agonists in the rat | journal = Neuropeptides | volume = 5 | issue = 1–3 | pages = 11–4 | date = December 1984 | pmid = 6152317 | doi = 10.1016/0143-4179(84)90014-3 | s2cid = 31842402 }}{{cite journal | vauthors = Howes JF, Villarreal JE, Harris LS, Essigmann EM, Cowan A | title = Xorphanol | journal = Drug and Alcohol Dependence | volume = 14 | issue = 3–4 | pages = 373–80 | date = February 1985 | pmid = 4039650 | doi = 10.1016/0376-8716(85)90068-7 }} 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.{{cite journal | vauthors = Porter MC, Hartnagel RE, Clemens GR, Kowalski RL, Bare JJ, Halliwell WE, Kitchen DN | title = Preclinical toxicity and teratogenicity studies with the narcotic antagonist analgesic drug TR5379M | journal = Fundamental and Applied Toxicology | volume = 3 | issue = 5 | pages = 478–82 | year = 1983 | pmid = 6642105 | doi = 10.1016/S0272-0590(83)80023-2 }} 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.[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] As a result of this dispute, the drug was never marketed commercially.