Synthesis and Pharmacological Activity of a Superagonist of the ORL-1 Receptor

Nociceptin (NC)/orphanin FQ (H-Phe-Gly-Gly-Phe-Thr-Gly-Ala-Arg-Lys-Ser-Ala-Arg-Lys-Leu-Ala-Asn-Gln-OH) is a neuropeptide, which modulates several biological functions by activating the ORL1 receptor [1]. In the past years, we have performed systematic structure activity studies on NC that have established: a) NC residues 1–13 are sufficient both for high ORL1 receptor binding and biological activity; b) The basic residues in the C-terminal sequence, especially Arg8, appear to be instrumental for ORL1 receptor recognition; c) Contrary to opioid peptides, which strictly require Tyrfor opioid receptor activation, the active core of NC that stimulates the ORL1 receptor, is the Phe4; d) Specific changes of the N-terminal sequence, expecially at Phe, led to the discovery of a partial agonist, [PheΨ(CH2-NH)Gly2]NC(1–13)-NH2, and [Nphe]NC(1–13)-NH2, a pure antagonist of the ORL1 receptor [2]. In the present investigation, we describe the effect of substitutions with a halogen series of the Phe4aromatic side chain of the NC(1–13)-NH2, and identification of new ligands, which behave as superagonists of the ORL1 receptor.