title: Designing bifunctional NOP receptor-mu opioid receptor ligands from NOP-receptor selective scaffolds. Part II.
abstract: The nociceptin opioid receptor (NOP) and its endogenous peptide ligand nociceptin/orphanin FQ have been shown to modulate the pharmacological effects of the classical opioid receptor system. Suppression of opioid-induced reward associated with mu-opioid receptor (MOP)-mediated analgesia, without decreasing anti-nociceptive efficacy, can potentially be achieved with NOP agonists having bifunctional agonist activity at MOP, to afford 'non-addicting' analgesics. In Part II of this series, we describe a continuing structure-activity relationship (SAR) study of the NOP-selective piperidin-4-yl-1,3-dihydroindol-2-one scaffold, to obtain bifunctional activity at MOP, and a suitable ratio of NOP/MOP agonist activity that produces a non-addicting analgesic profile. The SAR reported here is focused on the influence of various piperidine nitrogen aromatic substituents on the ratio of binding affinity and intrinsic activity at both the NOP and MOP receptors.
authors.affiliation: Astraea Therapeutics, LLC., 320 Logue Avenue, Mountain View, CA 94043, United States.
authors.forename: V Blair
authors.initials: VB
authors.lastname: Journigan
authors.affiliation: SRI International, Biosciences Division, 333 Ravenswood Avenue, Menlo Park, CA 94025, United States.
authors.forename: Willma E
authors.initials: WE
authors.lastname: Polgar
authors.affiliation: SRI International, Biosciences Division, 333 Ravenswood Avenue, Menlo Park, CA 94025, United States.
authors.forename: Taline V
authors.initials: TV
authors.lastname: Khroyan
authors.affiliation: Astraea Therapeutics, LLC., 320 Logue Avenue, Mountain View, CA 94043, United States. Electronic address: nurulain@astraeatherapeutics.com.
authors.forename: Nurulain T
authors.initials: NT
authors.lastname: Zaveri
mesh_terms: D000700:Analgesics / Q000737:chemistry* / Q000378:metabolism / Q000627:therapeutic use; D000818:Animals; D008024:Ligands; D051379:Mice; D023421:Models, Animal; D010146:Pain / Q000188:drug therapy; D010880:Piperidines / Q000737:chemistry; 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: D000700:Analgesics; D008024:Ligands; D010880:Piperidines; D011957:Receptors, Opioid; D017450:Receptors, Opioid, mu; C032727:piperidine; D000094942:Nociceptin Receptor; C000722287:Oprl1 protein, mouse
keywords: Bifunctional ligands; N/OFQ; NOP/opioid; Nociceptin receptor; Nociceptin/orphanin FQ