title: A selective small molecule NOP (ORL-1 receptor) partial agonist for the treatment of anxiety.
abstract: Small molecule (1) has been identified as a selective partial agonist of Opioid Receptor Like-1 (ORL-1) with potential utility for the treatment of anxiety and other disorders. Nociceptin (orphanin FQ) is an endogenous peptide ligand that binds to ORL-1, however it does not bind the classical δ, μ and κ opioid receptors with high affinity. The synthesis of 1 involved using a molecular diversity approach, to rapidly advance a library of compounds for biological testing. A lead selective potent partial agonist (35-fold ORL-1/Mu) progressed to ORL-1 (NOP or OP4) proof of concept testing in advanced studies. The synthetic approach and biological data for the related chemical series will be presented.
authors.affiliation: West Chester University, Chemistry Department, West Chester, PA, USA. Electronic address: tross@wcupa.edu.
authors.forename: Tina Morgan
authors.initials: TM
authors.lastname: Ross
authors.affiliation: Ace Glass, Vineland, NJ, USA.
authors.forename: Kathleen
authors.initials: K
authors.lastname: Battista
authors.affiliation: Johnson & Johnson Pharmaceutical Research and Development, LLC, Spring House, PA, USA.
authors.forename: Gilles C
authors.initials: GC
authors.lastname: Bignan
authors.affiliation: Fox Chase Chemical Diversity Center, Doylestown, PA, USA.
authors.forename: Doug E
authors.initials: DE
authors.lastname: Brenneman
authors.affiliation: Johnson & Johnson Pharmaceutical Research and Development, LLC, Spring House, PA, USA.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Connolly
authors.affiliation: Sanofi-Aventis, Boston, MA, USA.
authors.forename: Jingchun
authors.initials: J
authors.lastname: Liu
authors.affiliation: Hoffmann La-Roche, Nutley, NJ, USA.
authors.forename: Steven A
authors.initials: SA
authors.lastname: Middleton
authors.affiliation: Bristol-Myers Squibb, New Brunswick, NJ, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Orsini
authors.affiliation: Fox Chase Chemical Diversity Center, Doylestown, PA, USA.
authors.forename: Allen B
authors.initials: AB
authors.lastname: Reitz
authors.affiliation: Burlington Community College, Pemberton, NJ, USA.
authors.forename: Dan I
authors.initials: DI
authors.lastname: Rosenthal
authors.affiliation: Johnson & Johnson Pharmaceutical Research and Development, LLC, Spring House, PA, USA.
authors.forename: Malcolm K
authors.initials: MK
authors.lastname: Scott
authors.affiliation: Pfizer-Makro Technologies, Bridgewater, NJ, USA.
authors.forename: Anil H
authors.initials: AH
authors.lastname: Vaidya
mesh_terms: D000818:Animals; D001007:Anxiety / Q000188:drug therapy; D004195:Disease Models, Animal; D009043:Motor Activity / Q000187:drug effects; D018847:Opioid Peptides / Q000737:chemistry / Q000378:metabolism; D011485:Protein Binding; D051381:Rats; D011957:Receptors, Opioid / Q000819:agonists* / Q000378:metabolism; D054852:Small Molecule Libraries / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use; D013141:Spiro Compounds / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use; D013329:Structure-Activity Relationship; D000094942:Nociceptin Receptor; D000097629:Nociceptin
chemical_list: D018847:Opioid Peptides; D011957:Receptors, Opioid; D054852:Small Molecule Libraries; D013141:Spiro Compounds; D000094942:Nociceptin Receptor; D000097629:Nociceptin; C000601194:3-(3-(benzyl-butyl-amino)-2-hydroxypropyl)-8-cyclooctylmethyl-1-(4-fluorophenyl)-1,3,8-triazaspiro(4.5)decan-4-one; C000722285:Oprl1 protein, rat
keywords: Drug discovery; NOP receptor; Nociceptin; Opioid receptor-like receptor-1; Orphanin FQ