title: Designing bifunctional NOP receptor-mu opioid receptor ligands from NOP receptor-selective scaffolds. Part I.
abstract: The nociceptin receptor (NOP) and its endogenous agonist, nociceptin/orphanin FQ (N/OFQ), members of the opioid receptor and peptide families respectively, modulate the pharmacological effects of classical opioids, particularly opioid-induced reward and nociception. We hypothesized that compounds containing both NOP and opioid receptor activity in a single molecule may have useful pharmacological profiles as non-addicting analgesics or as drug abuse medications. We report here our forays into the structure-activity relationships for discovering 'bifunctional' NOP-mu opioid receptor (MOP) ligands, starting from our NOP-selective scaffolds. This initial SAR suggests pharmacophoric elements that may be modified to modulate/increase opioid affinity, while maintaining high affinity for the NOP receptor, to result in potent bifunctional small-molecule NOP/MOP ligands.
authors.affiliation: Astraea Therapeutics, LLC. 320 Logue Avenue, Mountain View, CA 94043, USA. nurulain@astraeatherapeutics.com
authors.forename: Nurulain T
authors.initials: NT
authors.lastname: Zaveri
authors.forename: Faming
authors.initials: F
authors.lastname: Jiang
authors.forename: Cris
authors.initials: C
authors.lastname: Olsen
authors.forename: Willma E
authors.initials: WE
authors.lastname: Polgar
authors.forename: Lawrence
authors.initials: L
authors.lastname: Toll
mesh_terms: D015195:Drug Design; D010880:Piperidines / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism; D011485:Protein Binding; D011957:Receptors, Opioid / Q000819:agonists* / Q000378:metabolism; D017450:Receptors, Opioid, mu / Q000819:agonists* / Q000378:metabolism; D013329:Structure-Activity Relationship; D000094942:Nociceptin Receptor
chemical_list: D010880:Piperidines; D011957:Receptors, Opioid; D017450:Receptors, Opioid, mu; C032727:piperidine; D000094942:Nociceptin Receptor