title: Opioid peptidomimetics: leads for the design of bioavailable mixed efficacy μ opioid receptor (MOR) agonist/δ opioid receptor (DOR) antagonist ligands.
abstract: We have previously described opioid peptidomimetic, 1, employing a tetrahydroquinoline scaffold and modeled on a series of cyclic tetrapeptide opioid agonists. We have recently described modifications to these peptides that confer a μ opioid receptor (MOR) agonist, δ opioid receptor (DOR) antagonist profile, which has been shown to reduce the development of tolerance to the analgesic actions of MOR agonists. Several such bifunctional ligands have been reported, but none has been demonstrated to cross the blood-brain barrier. Here we describe the transfer of structural features that evoked MOR agonist/DOR antagonist behavior in the cyclic peptides to the tetrahydroquinoline scaffold and show that the resulting peptidomimetics maintain the desired pharmacological profile. Further, the 4R diastereomer of 1 was fully efficacious and approximately equipotent to morphine in the mouse warm water tail withdrawal assay following intraperitoneal administration and thus a promising lead for the development of opioid analgesics with reduced tolerance.
authors: Department of Medicinal Chemistry, College of Pharmacy, University of Michigan, Ann Arbor, Michigan 48109, United States. him@umich.edu
authors: Henry I
authors: HI
authors: Mosberg
authors: Larisa
authors: L
authors: Yeomans
authors: Aubrie A
authors: AA
authors: Harland
authors: Aaron M
authors: AM
authors: Bender
authors: Katarzyna
authors: K
authors: Sobczyk-Kojiro
authors: Jessica P
authors: JP
authors: Anand
authors: Mary J
authors: MJ
authors: Clark
authors: Emily M
authors: EM
authors: Jutkiewicz
authors: John R
authors: JR
authors: Traynor
mesh_terms: D000700:Analgesics / Q000138:chemical synthesis / Q000494:pharmacology*; D000701:Analgesics, Opioid / Q000138:chemical synthesis*; D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D004361:Drug Tolerance / Q000502:physiology; D008024:Ligands; D051379:Mice; D057786:Peptidomimetics / Q000138:chemical synthesis*; D010666:Phenylpropionates / Q000138:chemical synthesis* / Q000494:pharmacology; D011804:Quinolines / Q000138:chemical synthesis* / Q000494:pharmacology; D051381:Rats; D017465:Receptors, Opioid, delta / Q000037:antagonists & inhibitors*; D017450:Receptors, Opioid, mu / Q000819:agonists*
chemical_list: C581010:2-amino-N-(6-benzyl-1,2,3,4-tetrahydroquinolin-4-yl)-3-(4-hydroxy-2,6-dimethylphenyl)propanamide; D000700:Analgesics; D000701:Analgesics, Opioid; D008024:Ligands; D057786:Peptidomimetics; D010666:Phenylpropionates; D011804:Quinolines; D017465:Receptors, Opioid, delta; D017450:Receptors, Opioid, mu