title: Further Optimization and Evaluation of Bioavailable, Mixed-Efficacy μ-Opioid Receptor (MOR) Agonists/δ-Opioid Receptor (DOR) Antagonists: Balancing MOR and DOR Affinities.
abstract: In a previously described peptidomimetic series, we reported the development of bifunctional μ-opioid receptor (MOR) agonist and δ-opioid receptor (DOR) antagonist ligands with a lead compound that produced antinociception for 1 h after intraperitoneal administration in mice. In this paper, we expand on our original series by presenting two modifications, both of which were designed with the following objectives: (1) probing bioavailability and improving metabolic stability, (2) balancing affinities between MOR and DOR while reducing affinity and efficacy at the κ-opioid receptor (KOR), and (3) improving in vivo efficacy. Here, we establish that, through N-acetylation of our original peptidomimetic series, we are able to improve DOR affinity and increase selectivity relative to KOR while maintaining the desired MOR agonist/DOR antagonist profile. From initial in vivo studies, one compound (14a) was found to produce dose-dependent antinociception after peripheral administration with an improved duration of action of longer than 3 h.
authors.affiliation: Interdepartmental Program in Medicinal Chemistry, ‡Department of Medicinal Chemistry, College of Pharmacy, and §Department of Pharmacology, Medical School, University of Michigan , Ann Arbor, Michigan 48109, United States.
authors.forename: Aubrie A
authors.initials: AA
authors.lastname: Harland
authors.affiliation: Interdepartmental Program in Medicinal Chemistry, ‡Department of Medicinal Chemistry, College of Pharmacy, and §Department of Pharmacology, Medical School, University of Michigan , Ann Arbor, Michigan 48109, United States.
authors.forename: Larisa
authors.initials: L
authors.lastname: Yeomans
authors.affiliation: Interdepartmental Program in Medicinal Chemistry, ‡Department of Medicinal Chemistry, College of Pharmacy, and §Department of Pharmacology, Medical School, University of Michigan , Ann Arbor, Michigan 48109, United States.
authors.forename: Nicholas W
authors.initials: NW
authors.lastname: Griggs
authors.affiliation: Interdepartmental Program in Medicinal Chemistry, ‡Department of Medicinal Chemistry, College of Pharmacy, and §Department of Pharmacology, Medical School, University of Michigan , Ann Arbor, Michigan 48109, United States.
authors.forename: Jessica P
authors.initials: JP
authors.lastname: Anand
authors.affiliation: Interdepartmental Program in Medicinal Chemistry, ‡Department of Medicinal Chemistry, College of Pharmacy, and §Department of Pharmacology, Medical School, University of Michigan , Ann Arbor, Michigan 48109, United States.
authors.forename: Irina D
authors.initials: ID
authors.lastname: Pogozheva
authors.affiliation: Interdepartmental Program in Medicinal Chemistry, ‡Department of Medicinal Chemistry, College of Pharmacy, and §Department of Pharmacology, Medical School, University of Michigan , Ann Arbor, Michigan 48109, United States.
authors.forename: Emily M
authors.initials: EM
authors.lastname: Jutkiewicz
authors.affiliation: Interdepartmental Program in Medicinal Chemistry, ‡Department of Medicinal Chemistry, College of Pharmacy, and §Department of Pharmacology, Medical School, University of Michigan , Ann Arbor, Michigan 48109, United States.
authors.forename: John R
authors.initials: JR
authors.lastname: Traynor
authors.affiliation: Interdepartmental Program in Medicinal Chemistry, ‡Department of Medicinal Chemistry, College of Pharmacy, and §Department of Pharmacology, Medical School, University of Michigan , Ann Arbor, Michigan 48109, United States.
authors.forename: Henry I
authors.initials: HI
authors.lastname: Mosberg
mesh_terms: D000107:Acetylation; D000700:Analgesics / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D001682:Biological Availability; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000378:metabolism; D006801:Humans; D007274:Injections, Intraperitoneal; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010147:Pain Measurement / Q000187:drug effects; D011869:Radioligand Assay; D017465:Receptors, Opioid, delta / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D017473:Receptors, Opioid, kappa / Q000378:metabolism; D017450:Receptors, Opioid, mu / Q000819:agonists* / Q000737:chemistry / Q000378:metabolism; D013329:Structure-Activity Relationship; D013379:Substrate Specificity
chemical_list: D000700:Analgesics; D017465:Receptors, Opioid, delta; D017473:Receptors, Opioid, kappa; D017450:Receptors, Opioid, mu; D016244:Guanosine 5'-O-(3-Thiotriphosphate)