Characterization of opiates, neuroleptics, and synthetic analogs at ORL1 and opioid receptors

Nociceptin/orphanin FQ (N/OFQ) was recently identified as the endogenous li gand for the opioid-receptor like (ORL1) receptor. Although the ORL1 recept or shows sequence homology with the opioid receptors, the nociceptin/ORL1 l igand-receptor system has very distinct pharmacological actions compared to the opioid receptor system. Recently, several small-molecule ORL1 receptor ligands were reported by pharmaceutical companies. Most of these ligands h ad close structural similarities with known neuroleptics and opiates. In th is study, we screened several available neuroleptics and opiates for their binding affinity and functional activity at ORL1 and the opioid receptors. We also synthesized several analogs of known opiates with modified piperidi ne N-substituents in order to characterize the ORL1 receptor ligand binding pocket. Substitution with the large, lipophilic cyclooctylmethyl moiety in creased ORL1 receptor affinity and decreased mu receptor affinity and effic acy in the fentanyl series of ligands but had a different effect in the ori pavine class of opiate ligands. Our results indicate that opiates and neuro leptics may be good starting points for ORL1 receptor ligand design, and th e selectivity may be modulated by appropriate structural modifications. (C) 2001 Elsevier Science B.V. All rights reserved.