| 词条 | Xorphanol |
| 释义 |
| Verifiedfields = changed | Watchedfields = changed | verifiedrevid = 448118966 | IUPAC_name = N-(Cyclobutylmethyl)-8β-methyl-6-methylenemorphinan-3-ol | image = Xorphanol.svg | alt = Structural formula | width = 205 | image2 = Xorphanol molecule ball.png | alt2 = Ball-and-stick model | width2 = 220 | tradename = | pregnancy_AU = | pregnancy_US = | pregnancy_category = | legal_AU = | legal_CA = | legal_UK = | legal_US = | legal_status = | routes_of_administration = | bioavailability = | protein_bound = | metabolism = | elimination_half-life = | excretion = | CAS_number_Ref = {{cascite|correct|??}} | CAS_number = 77287-89-9 | ATC_prefix = none | ATC_suffix = | PubChem = 5488631 | DrugBank_Ref = {{drugbankcite|correct|drugbank}} | DrugBank = | UNII_Ref = {{fdacite|correct|FDA}} | UNII = L415991P58 | ChemSpiderID_Ref = {{chemspidercite|changed|chemspider}} | ChemSpiderID = 20121496 | C=23 | H=31 | N=1 | O=1 | molecular_weight = 337.498 g/mol | smiles = C[C@H]1CC(=C)C[C@@]23[C@@H]1[C@@H](CC4=C2C=C(C=C4)O)N(CC3)CC5CCC5 | StdInChI_Ref = {{stdinchicite|changed|chemspider}} | 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 | StdInChIKey_Ref = {{stdinchicite|changed|chemspider}} | StdInChIKey = AZJPPZHRNFQRRE-AZIXLERZSA-N }}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 (Ki = 0.4 nM; EC50 = 3.3 nM; {{abbr|Imax|maximum inhibition}} = 49%; {{abbr|IA|relative intrinsic activity}} = 0.84)[7][8][9] and to a lesser extent as a partial agonist of the μ-opioid receptor (Ki = 0.25 nM; IC50 = 3.4 nM; {{abbr|Imax|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).[3][10] The drug has also been found to act as an agonist of the δ-opioid receptor (Ki = 1.0 nM; IC50 = 8 nM; {{abbr|Imax|maximum inhibition}} = 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
References1. ^{{cite book|author1=Dr. Ian Morton|author2=I.K. Morton|author3=Judith M. Hall|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–}} {{Hallucinogens}}{{Opioidergics}}{{analgesic-stub}}2. ^{{cite book|title=ANNUAL REPORTS IN MED CHEMISTRY V25 PPR|url=https://books.google.com/books?id=NZZbEkldeJAC&pg=PA12|date=10 October 1990|publisher=Academic Press|isbn=978-0-08-058369-3|pages=12–}} 3. ^1 {{cite book|author=Daniel Lednicer|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}} 4. ^{{cite book|author1=Deborah L. Colbern|author2=Willem Hendrik Gispen|author3=New York Academy of Sciences|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}} 5. ^{{cite journal|last1=Gmerek|first1=Debra E.|last2=Cowan|first2=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|year=1988|pages=291–300|issn=0077-8923|doi=10.1111/j.1749-6632.1988.tb38614.x}} 6. ^{{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 Res. Monogr. | volume = 67 | issue = | pages = 132–7 | year = 1986 | pmid = 3018570 | doi = | url = }} 7. ^{{cite journal|last1=Gharagozlou|first1=Parham|last2=Hashemi|first2=Ezzat|last3=DeLorey|first3=TimothyM|last4=Clark|first4=J David|last5=Lameh|first5=Jelveh|title=Pharmacological profiles of opioid ligands at Kappa opioid receptors|journal=BMC Pharmacology|volume=6|issue=1|year=2006|pages=3|issn=1471-2210|doi=10.1186/1471-2210-6-3|pmid=16433932|pmc=1403760}} 8. ^{{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–}} 9. ^{{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 Pharmacol. | volume = 3 | issue = | pages = 1 | year = 2003 | pmid = 12513698 | pmc = 140036 | doi = 10.1186/1471-2210-3-1 | url = }} 10. ^{{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–}} 11. ^{{cite journal|last1=Gharagozlou|first1=Parham|last2=Demirci|first2=Hasan|last3=Clark|first3=J|last4=Lameh|first4=Jelveh|title=Activation profiles of opioid ligands in HEK cells expressing δ opioid receptors|journal=BMC Neuroscience|volume=3|issue=1|year=2002|pages=19|issn=1471-2202|doi=10.1186/1471-2202-3-19}} 12. ^{{cite journal | last1 = Polazzi | first1 = JO | last2 = Kotick | first2 = MP | last3 = Howes | first3 = JF | last4 = Bousquet | first4 = 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 | year = 1981 | pmid = 6796691 | doi=10.1021/jm00144a029}} 13. ^{{cite journal | last1 = McCarthy | first1 = PS | last2 = Howlett | first2 = GJ | title = Physical dependence induced by opiate partial agonists in the rat | journal = Neuropeptides | volume = 5 | issue = 1–3 | pages = 11–4 | year = 1984 | pmid = 6152317 | doi=10.1016/0143-4179(84)90014-3}} 14. ^{{cite journal | last1 = Howes | first1 = JF | last2 = Villarreal | first2 = JE | last3 = Harris | first3 = LS | last4 = Essigmann | first4 = EM | last5 = Cowan | first5 = A | title = Xorphanol | journal = Drug and Alcohol Dependence | volume = 14 | issue = 3–4 | pages = 373–80 | year = 1985 | pmid = 4039650 | doi=10.1016/0376-8716(85)90068-7}} 15. ^{{cite journal | last1 = Porter | first1 = MC | last2 = Hartnagel | first2 = RE | last3 = Clemens | first3 = GR | last4 = Kowalski | first4 = RL | last5 = Bare | first5 = JJ | last6 = Halliwell | first6 = WE | last7 = Kitchen | first7 = 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 }} 16. ^Maruho Company Ltd v Miles Inc (1993) 13 F.3d 6 9 : Analgesics|Convulsants|Delta-opioid agonists|Dissociative drugs|Kappa agonists|Morphinans|Phenols|Semisynthetic opioids|Cyclobutanes |
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