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Title: Ro64-6198  
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Subject: Kobret, 6β-Naltrexol-d4, Hemorphin, Naloxonazine, Gemazocine
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Systematic (IUPAC) name
Clinical data
Legal status
ATC code ?
IUPHAR ligand
ChemSpider  N
Synonyms Ro64-6198
Chemical data
Formula C26H31N3O 
Mol. mass 401.543 g/mol

Ro64-6198 is an nociceptoid drug used in scientific research. It acts as a potent and selective agonist for the nociceptin receptor, also known as the ORL-1 (opiate receptor like-1) receptor, with over 100x selectivity over other opioid receptors.[1] It produces anxiolytic effects in animal studies equivalent to those of benzodiazepine drugs,[2] but has no anticonvulsant effects and does not produce any overt effects on behaviour.[3] However it does impair short-term memory,[4] and counteracts stress-induced anorexia.[5][6] It also has antitussive effects,[7] and reduces the rewarding and analgesic effects of morphine, although it did not prevent the development of dependence.[8][9][10] It has been shown to reduce alcohol self-administration in animals and suppressed relapses in animal models of alcoholism, and ORL-1 agonists may have application in the treatment of alcoholism.[11]

Ro64-6198 was able to be recognised as a discriminative stimulus by rats distinct from other opioid receptor ligands,[12] but was not able to produce the conditioned place preference thought to be indicative of addictive potential.[13] Consequently while the role of ORL-1 receptors in the body is complex and remains poorly understood, Ro64-6198 has demonstrated multiple pharmacological actions and has been very useful in the study of the ORL-1 receptor system, especially in relation to anxiety and anorexia; however, due to poor oral bioavailability, Ro 64-6198 will most likely not be pursued clinically.[14] Studies in primates showed it to have analgesic effects but without producing respiratory depression or reinforcing effects.[15]


  1. ^ Dautzenberg FM, Wichmann J, Higelin J, Py-Lang G, Kratzeisen C, Malherbe P, Kilpatrick GJ, Jenck F. Pharmacological characterization of the novel nonpeptide orphanin FQ/nociceptin receptor agonist Ro 64-6198: rapid and reversible desensitization of the ORL1 receptor in vitro and lack of tolerance in vivo. Journal of Pharmacology and Experimental Therapeutics. 2001 Aug;298(2):812-9. PMID 11454946
  2. ^ Varty GB, Hyde LA, Hodgson RA, Lu SX, McCool MF, Kazdoba TM, Del Vecchio RA, Guthrie DH, Pond AJ, Grzelak ME, Xu X, Korfmacher WA, Tulshian D, Parker EM, Higgins GA. Characterization of the nociceptin receptor (ORL-1) agonist, Ro64-6198, in tests of anxiety across multiple species. Psychopharmacology (Berlin). 2005 Oct;182(1):132-43. PMID 16025321
  3. ^ Jenck F, Wichmann J, Dautzenberg FM, Moreau JL, Ouagazzal AM, Martin JR, Lundstrom K, Cesura AM, Poli SM, Roever S, Kolczewski S, Adam G, Kilpatrick G. A synthetic agonist at the orphanin FQ/nociceptin receptor ORL1: anxiolytic profile in the rat. Proceedings of the National Academy of Sciences USA. 2000 Apr 25;97(9):4938-43. doi:10.1073/pnas.090514397 PMID 10758169
  4. ^ Higgins GA, Kew JN, Richards JG, Takeshima H, Jenck F, Adam G, Wichmann J, Kemp JA, Grottick AJ. A combined pharmacological and genetic approach to investigate the role of orphanin FQ in learning and memory. European Journal of Neuroscience. 2002 Mar;15(5):911-22. PMID 11906533
  5. ^ Ciccocioppo R, Biondini M, Antonelli L, Wichmann J, Jenck F, Massi M. Reversal of stress- and CRF-induced anorexia in rats by the synthetic nociceptin/orphanin FQ receptor agonist, Ro 64-6198. Psychopharmacology (Berlin). 2002 May;161(2):113-9. PMID 11981590
  6. ^ Ciccocioppo R, Cippitelli A, Economidou D, Fedeli A, Massi M. Nociceptin/orphanin FQ acts as a functional antagonist of corticotropin-releasing factor to inhibit its anorectic effect. Physiology and Behaviour. 2004 Aug;82(1):63-8. PMID 15234592
  7. ^ McLeod RL, Jia Y, Fernandez X, Parra LE, Wang X, Tulshian DB, Kiselgof EJ, Tan Z, Fawzi AB, Smith-Torhan A, Zhang H, Hey JA. Antitussive profile of the NOP agonist Ro-64-6198 in the guinea pig. Pharmacology. 2004 Jul;71(3):143-9. PMID 15161996
  8. ^ Kotlinska J, Wichmann J, Rafalski P, Talarek S, Dylag T, Silberring J. Non-peptidergic OP4 receptor agonist inhibits morphine antinociception but does not influence morphine dependence. Neuroreport. 2003 Mar 24;14(4):601-4. PMID 12657894
  9. ^ Shoblock JR, Wichmann J, Maidment NT. The effect of a systemically active ORL-1 agonist, Ro 64-6198, on the acquisition, expression, extinction, and reinstatement of morphine conditioned place preference. Neuropharmacology. 2005 Sep;49(4):439-46. PMID 15919100
  10. ^ Reiss D, Wichmann J, Tekeshima H, Kieffer BL, Ouagazzal AM. Effects of nociceptin/orphanin FQ receptor (NOP) agonist, Ro64-6198, on reactivity to acute pain in mice: comparison to morphine. European Journal of Pharmacology. 2008 Jan 28;579(1-3):141-8. PMID 18031727
  11. ^ Kuzmin A, Kreek MJ, Bakalkin G, Liljequist S. The nociceptin/orphanin FQ receptor agonist Ro 64-6198 reduces alcohol self-administration and prevents relapse-like alcohol drinking. Neuropsychopharmacology. 2007 Apr;32(4):902-10. PMID 16880770
  12. ^ Recker MD, Higgins GA. The opioid receptor like-1 receptor agonist Ro 64-6198 (1S,3aS-8-2,3,3a,4,5,6-hexahydro-1H-phenalen-1-yl-1-phenyl-1,3,8-triaza-spiro[4.5]decan-4-one) produces a discriminative stimulus in rats distinct from that of a mu, kappa, and delta opioid receptor agonist cue. Journal of Pharmacology and Experimental Therapeutics. 2004 Nov;311(2):652-8. PMID 15226383
  13. ^ Le Pen G, Wichmann J, Moreau JL, Jenck F. The orphanin receptor agonist RO 64-6198 does not induce place conditioning in rats. Neuroreport. 2002 Mar 25;13(4):451-4. PMID 11930159
  14. ^ Shoblock JR. The pharmacology of Ro 64-6198, a systemically active, nonpeptide NOP receptor (opiate receptor-like 1, ORL-1) agonist with diverse preclinical therapeutic activity. CNS Drug Reviews. 2007 Spring;13(1):107-36. PMID 17461893
  15. ^ Ko MC, Woods JH, Fantegrossi WE, Galuska CM, Wichmann J, Prinssen EP (March 2009). "Behavioral Effects of a Synthetic Agonist Selective for Nociceptin/Orphanin FQ Peptide Receptors in Monkeys". Neuropsychopharmacology 34 (9): 2088–96.  

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