ORL1 receptor agonists

Higgins, G.A., Grottick, A.J., Ballard, T.M., Richards, J.G., Messer, J., Takeshima, H., Pauly-Evers, M., Jenck, F., Adam, G., Wichmann, J. Influence of the selective ORL1 receptor agonist, Ro64-6198, on rodent neurological function, Neruopharmacology 2001, 41, 97-107. 

Ito, F., Kondo, H., Noguchi, H., Ohashi, Y. (Pfizer Inc.) 4-(2-Keto-1-benzimidazolinyl)piperidine compounds as ORL1 -receptor agonists, W09936421 (1999). 

Meunier, J.C., Mollereau, C., Toll, L., Suaudeau, C., Moisand, C., Alvinerie, P., Butour, J.L., Guillemot, J.C., Ferrara, P., Monsarrat, B. Isolation and structure of the endogenous agonist of opioid receptorlike ORL1 receptor, Nature 1995, 377, 532-535. 

Opioid receptor binding Buprenorphine has a mixed agonistic-antagonistic action profile with a high affinity for the p-, k-, and 5-opioid receptors (Huang et al., 2001). An approximately 100-fold lower affinity was observed for the ORL1-receptor. The compound dissociates slowly from the receptor which may explain some peculiarities in its pharmacological actions. 

Dautzenberg, F.M., Wichmann, J., Higelin, J., Py-Lang, G., Kratzeisen, C., Malherbe, P., Kilpatrick, G.J., Jenck, F. Pharmacological characterization of the novel nonpetide orphanin FQ / nociceptin receptor agonist Ro 64-6198 Rapid and reversible desensitization of the ORL1 receptor in vitro and lack of tolerance in vivo, J. Pharmacol. Exp. Ther. 2001, 298, 812-819. 

Broer, B.M., Gurrath, M., Holtje, H.-D. Molecular modeling studies on the ORL1-receptor and ORL1-agonists. 

Meunier JC, Mollereau C, Toll L, et al. Isolation and structure of the endogenous agonist of opioid receptor-like ORL1 receptor. Nature 1995 377 532-535. 

The heptadecapeptide nociceptin has some structural similarity to dynorphin A (YGGFLRRIRPKLKWDNQ Darland et al., 1998), but bears an N-terminal phenylalanine (F) instead of tyrosine (Y) which is essential for the activation of classical opioid receptors ( n, k, 5). It was named nociceptin (NC) by Meunier et al. (1995) to indicate its initially observed hyperalgesic effect and is the endogenous agonist of ORL1. 

Further ORL1 antagonists include a series of NalBzOH analogs where the benzoylhydrazone moiety is replaced by hydroxylamides (cpd. 2). These compounds are also claimed to have agonistic activity at a, k and 8 receptors. 

Pomonis, J.D., Billington, C.J., Levine, A.S. Orphanin FQ, agonist of orphan opioid receptor ORL1, stimulates feeding in rats, NeuroReport 1996, 8, 369-371. 

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