Ro64-6198

Ro64-6198 is a 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
Clinical data
Other namesRo64-6198
Identifiers
IUPAC name
  • 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)
SMILES
  • C1C[C@H]2CC[C@@H](C3=CC=CC(=C23)C1)N4CCC5(CC4)C(=O)NCN5C6=CC=CC=C6
InChI
  • 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
 NY (what is this?)  (verify)

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. Frank M. Dautzenberg, Jürgen Wichmann, Jacqueline Higelin, Gabrielle Py-Lang, Claudia Kratzeisen, Pari Malherbe, Gavin J. Kilpatrick, Francois Jenck (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". Journal of Pharmacology and Experimental Therapeutics. 298 (2): 812–819. PMID 11454946.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  2. Varty, G. B.; Hyde, L. A.; Hodgson, R. A.; Lu, S. X.; McCool, M. F.; Kazdoba, T. M.; Del Vecchio, R. A.; Guthrie, D. H.; Pond, A. J.; Grzelak, M. E.; Xu, X.; Korfmacher, W. A.; Tulshian, D.; Parker, E. M.; Higgins, G. A. (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. ISSN 0033-3158. PMID 16025321. S2CID 20493194.
  3. Jenck, F.; Wichmann, J.; Dautzenberg, F. M.; Moreau, J.-L.; Ouagazzal, A. M.; Martin, J. R.; Lundstrom, K.; Cesura, A. M.; Poli, S. M.; Roever, S.; Kolczewski, S.; Adam, G.; Kilpatrick, G. (2000). "A synthetic agonist at the orphanin FQ/nociceptin receptor ORL1: Anxiolytic profile in the rat". Proceedings of the National Academy of Sciences. 97 (9): 4938–4943. Bibcode:2000PNAS...97.4938J. doi:10.1073/pnas.090514397. ISSN 0027-8424. PMC 18336. PMID 10758169.
  4. Higgins, G. A.; Kew, J. N. C.; Richards, J. G.; Takeshima, H.; Jenck, F.; Adam, G.; Wichmann, J.; Kemp, J. A.; Grottick, A. J. (2002). "A combined pharmacological and genetic approach to investigate the role of orphanin FQ in learning and memory". European Journal of Neuroscience. 15 (5): 911–922. doi:10.1046/j.1460-9568.2002.01926.x. ISSN 0953-816X. PMID 11906533. S2CID 20973698.
  5. Ciccocioppo, Roberto; Biondini, Michela; Antonelli, Lorena; Wichmann, Juergen; Jenck, François; Massi, Maurizio (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. ISSN 0033-3158. PMID 11981590. S2CID 26808279.
  6. Ciccocioppo, Roberto; Cippitelli, Andrea; Economidou, Daina; Fedeli, Amalia; Massi, Maurizio (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. ISSN 0031-9384. PMID 15234592. S2CID 26035134.
  7. McLeod, Robbie L.; Jia, Yanlin; Fernandez, Xiomara; Parra, Leonard E.; Wang, Xin; Tulshian, Deen B.; Kiselgof, Eugenia J.; Tan, Zheng; Fawzi, Ahmad B.; Smith-Torhan, April; Zhang, Hongtao; Hey, John A. (2004). "Antitussive Profile of the NOP Agonist Ro-64-6198 in the Guinea Pig". Pharmacology. 71 (3): 143–149. doi:10.1159/000077448. ISSN 0031-7012. PMID 15161996. S2CID 19512178.
  8. Kotlinska, Jolanta; Wichmann, Juergen; Rafalski, Piotr; Talarek, Sylwia; Dylag, Tomasz; Silberring, Jerzy (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. ISSN 0959-4965. PMID 12657894. S2CID 25805180.
  9. Shoblock, J; Wichmann, J; Maidment, N (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. ISSN 0028-3908. PMID 15919100. S2CID 36459495.
  10. Reiss, David; Wichmann, Juergen; Tekeshima, Hiroshi; Kieffer, Brigitte L.; Ouagazzal, Abdel-Mouttalib (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. ISSN 0014-2999. PMID 18031727.
  11. Kuzmin, Alexander; Kreek, Mary Jeanne; Bakalkin, Georgy; Liljequist, Sture (2006). "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. ISSN 0893-133X. PMID 16880770.
  12. Recker, M. D. (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 μ, κ, and δ Opioid Receptor Agonist Cue". Journal of Pharmacology and Experimental Therapeutics. 311 (2): 652–658. doi:10.1124/jpet.104.071423. ISSN 0022-3565. PMID 15226383. S2CID 23849692.
  13. Le Pen, Gwenaëlle; Wichmann, Juergen; Moreau, Jean-Luc; Jenck, François (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. ISSN 0959-4965. PMID 11930159. S2CID 30616027.
  14. Shoblock, James R. (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. ISSN 1080-563X. PMC 6494153. 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. doi:10.1038/npp.2009.33. PMC 2804925. PMID 19279568.
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