Ro64-6198
Clinical data
Other namesRo64-6198
Identifiers
  • 8-[(1S,3aS)-2,3,3a,4,5,6-hexahydro-1H-phenalen-1-yl]-1-phenyl-1,3,8-triazaspiro[4.5]decan-4-one
CAS Number
PubChem CID
IUPHAR/BPS
ChemSpider
ChEMBL
Chemical and physical data
FormulaC26H31N3O
Molar mass401.554 g·mol−1
3D model (JSmol)
  • C1C[C@H]2CC[C@@H](C3=CC=CC(=C23)C1)N4CCC5(CC4)C(=O)NCN5C6=CC=CC=C6
  • InChI=1S/C26H31N3O/c30-25-26(29(18-27-25)21-9-2-1-3-10-21)14-16-28(17-15-26)23-13-12-20-7-4-6-19-8-5-11-22(23)24(19)20/h1-3,5,8-11,20,23H,4,6-7,12-18H2,(H,27,30)/t20-,23-/m0/s1 ☒N
  • Key:JLFMYEAXZNPWBK-REWPJTCUSA-N ☒N
 ☒NcheckY (what is this?)  (verify)

Ro64-6198 is an opioid 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 the 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]

References

  1. ^ Dautzenberg FM, Wichmann J, Higelin J, Py-Lang G, Kratzeisen C, Malherbe P, et al. (August 2001). "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". The Journal of Pharmacology and Experimental Therapeutics. 298 (2): 812–819. PMID 11454946.
  2. ^ Varty GB, Hyde LA, Hodgson RA, Lu SX, McCool MF, Kazdoba TM, et al. (October 2005). "Characterization of the nociceptin receptor (ORL-1) agonist, Ro64-6198, in tests of anxiety across multiple species". Psychopharmacology. 182 (1): 132–143. doi:10.1007/s00213-005-0041-4. PMID 16025321. S2CID 20493194.
  3. ^ Jenck F, Wichmann J, Dautzenberg FM, Moreau JL, Ouagazzal AM, Martin JR, et al. (April 2000). "A synthetic agonist at the orphanin FQ/nociceptin receptor ORL1: anxiolytic profile in the rat". Proceedings of the National Academy of Sciences of the United States of America. 97 (9): 4938–4943. Bibcode:2000PNAS...97.4938J. doi:10.1073/pnas.090514397. PMC 18336. PMID 10758169.
  4. ^ Higgins GA, Kew JN, Richards JG, Takeshima H, Jenck F, Adam G, et al. (March 2002). "A combined pharmacological and genetic approach to investigate the role of orphanin FQ in learning and memory". The European Journal of Neuroscience. 15 (5): 911–922. doi:10.1046/j.1460-9568.2002.01926.x. PMID 11906533. S2CID 20973698.
  5. ^ Ciccocioppo R, Biondini M, Antonelli L, Wichmann J, Jenck F, Massi M (May 2002). "Reversal of stress- and CRF-induced anorexia in rats by the synthetic nociceptin/orphanin FQ receptor agonist, Ro 64-6198". Psychopharmacology. 161 (2): 113–119. doi:10.1007/s00213-002-1020-7. PMID 11981590. S2CID 26808279.
  6. ^ Ciccocioppo R, Cippitelli A, Economidou D, Fedeli A, Massi M (August 2004). "Nociceptin/orphanin FQ acts as a functional antagonist of corticotropin-releasing factor to inhibit its anorectic effect". Physiology & Behavior. 82 (1): 63–68. doi:10.1016/j.physbeh.2004.04.035. PMID 15234592. S2CID 26035134.
  7. ^ McLeod RL, Jia Y, Fernandez X, Parra LE, Wang X, Tulshian DB, et al. (July 2004). "Antitussive profile of the NOP agonist Ro-64-6198 in the guinea pig". Pharmacology. 71 (3): 143–149. doi:10.1159/000077448. PMID 15161996. S2CID 19512178.
  8. ^ Kotlinska J, Wichmann J, Rafalski P, Talarek S, Dylag T, Silberring J (March 2003). "Non-peptidergic OP4 receptor agonist inhibits morphine antinociception but does not influence morphine dependence". NeuroReport. 14 (4): 601–604. doi:10.1097/00001756-200303240-00015. PMID 12657894. S2CID 25805180.
  9. ^ Shoblock JR, Wichmann J, Maidment NT (September 2005). "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. 49 (4): 439–446. doi:10.1016/j.neuropharm.2005.04.008. PMID 15919100. S2CID 36459495.
  10. ^ Reiss D, Wichmann J, Tekeshima H, Kieffer BL, Ouagazzal AM (January 2008). "Effects of nociceptin/orphanin FQ receptor (NOP) agonist, Ro64-6198, on reactivity to acute pain in mice: comparison to morphine". European Journal of Pharmacology. 579 (1–3): 141–148. doi:10.1016/j.ejphar.2007.10.031. PMID 18031727.
  11. ^ Kuzmin A, Kreek MJ, Bakalkin G, Liljequist S (April 2007). "The nociceptin/orphanin FQ receptor agonist Ro 64-6198 reduces alcohol self-administration and prevents relapse-like alcohol drinking". Neuropsychopharmacology. 32 (4): 902–910. doi:10.1038/sj.npp.1301169. PMID 16880770.
  12. ^ Recker MD, Higgins GA (November 2004). "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". The Journal of Pharmacology and Experimental Therapeutics. 311 (2): 652–658. doi:10.1124/jpet.104.071423. PMID 15226383. S2CID 23849692.
  13. ^ Le Pen G, Wichmann J, Moreau JL, Jenck F (March 2002). "The orphanin receptor agonist RO 64-6198 does not induce place conditioning in rats". NeuroReport. 13 (4): 451–454. doi:10.1097/00001756-200203250-00018. PMID 11930159. S2CID 30616027.
  14. ^ Shoblock JR (2007). "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. 13 (1): 107–136. doi:10.1111/j.1527-3458.2007.00007.x. PMC 6494153. PMID 17461893.
  15. ^ Ko MC, Woods JH, Fantegrossi WE, Galuska CM, Wichmann J, Prinssen EP (August 2009). "Behavioral effects of a synthetic agonist selective for nociceptin/orphanin FQ peptide receptors in monkeys". Neuropsychopharmacology. 34 (9): 2088–2096. doi:10.1038/npp.2009.33. PMC 2804925. PMID 19279568.
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