title: Synthesis and evaluation of 4-substituted piperidines and piperazines as balanced affinity μ opioid receptor (MOR) agonist/δ opioid receptor (DOR) antagonist ligands.
abstract: In this letter, we describe a series of 4-substituted piperidine and piperazine compounds based on tetrahydroquinoline 1, a compound that shows balanced, low nanomolar binding affinity for the mu opioid receptor (MOR) and the delta opioid receptor (DOR). We have shown that by changing the length and flexibility profile of the side chain in this position, binding affinity is improved at both receptors by a significant degree. Furthermore, several of the compounds described herein display good efficacy at MOR, while simultaneously displaying DOR antagonism. The MOR agonist/DOR antagonist has shown promise in the reduction of negative side effects displayed by selective MOR agonists, namely the development of dependence and tolerance.
authors.affiliation: Department of Medicinal Chemistry, College of Pharmacy, University of Michigan, Ann Arbor, MI 48109, United States; Interdepartmental Program in Medicinal Chemistry, University of Michigan, Ann Arbor, MI 48109, United States.
authors.forename: Aaron M
authors.initials: AM
authors.lastname: Bender
authors.affiliation: Department of Pharmacology, Medical School, University of Michigan, Ann Arbor, MI 48109, United States.
authors.forename: Mary J
authors.initials: MJ
authors.lastname: Clark
authors.affiliation: Department of Medicinal Chemistry, College of Pharmacy, University of Michigan, Ann Arbor, MI 48109, United States; Interdepartmental Program in Medicinal Chemistry, University of Michigan, Ann Arbor, MI 48109, United States.
authors.forename: Michael P
authors.initials: MP
authors.lastname: Agius
authors.affiliation: Department of Pharmacology, Medical School, University of Michigan, Ann Arbor, MI 48109, United States.
authors.forename: John R
authors.initials: JR
authors.lastname: Traynor
authors.affiliation: Department of Medicinal Chemistry, College of Pharmacy, University of Michigan, Ann Arbor, MI 48109, United States; Interdepartmental Program in Medicinal Chemistry, University of Michigan, Ann Arbor, MI 48109, United States. Electronic address: him@med.umich.edu.
authors.forename: Henry I
authors.initials: HI
authors.lastname: Mosberg
mesh_terms: D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D004353:Drug Evaluation, Preclinical / Q000379:methods; D010879:Piperazines / Q000138:chemical synthesis* / Q000378:metabolism; D010880:Piperidines / Q000138:chemical synthesis* / Q000378:metabolism; D011485:Protein Binding / Q000502:physiology; D017465:Receptors, Opioid, delta / Q000037:antagonists & inhibitors* / Q000378:metabolism; D017450:Receptors, Opioid, mu / Q000819:agonists* / Q000378:metabolism
chemical_list: D010879:Piperazines; D010880:Piperidines; D017465:Receptors, Opioid, delta; D017450:Receptors, Opioid, mu
keywords: Mixed function opioids; Opioid peptidomimetics