Asymmetric synthesis and in vitro and in vivo activity of tetrahydroquinolines featuring a diverse set of polar substitutions at the 6 position as mixed-efficacy μ opioid receptor/δ opioid receptor ligands.
We previously reported a small series of mixed-efficacy μ opioid receptor (MOR) agonist/δ opioid receptor (DOR) antagonist peptidomimetics featuring a tetrahydroquinoline scaffold and showed the promise of this series as effective analgesics after intraperitoneal administration in mice. We report here an expanded structure-activity relationship study of the pendant region of these compounds and focus in particular on the incorporation of heteroatoms into this side chain. These analogues provide new insight into the binding requirements for this scaffold at MOR, DOR, and the κ opioid receptor (KOR), and several of them (10j, 10k, 10m, and 10n) significantly improve upon the overall MOR agonist/DOR antagonist profile of our previous compounds. In vivo data for 10j, 10k, 10m, and 10n are also reported and show the antinociceptive potency and duration of action of compounds 10j and 10m to be comparable to those of morphine.
†Interdepartmental Program in Medicinal Chemistry, College of Pharmacy, University of Michigan, Ann Arbor, Michigan 48109, United States.
Aaron M
AM
Bender
‡Department of Pharmacology, School of Medicine, University of Michigan, Ann Arbor, Michigan 48109, United States.
Nicholas W
NW
Griggs
‡Department of Pharmacology, School of Medicine, University of Michigan, Ann Arbor, Michigan 48109, United States.
Jessica P
JP
Anand
‡Department of Pharmacology, School of Medicine, University of Michigan, Ann Arbor, Michigan 48109, United States.
John R
JR
Traynor
‡Department of Pharmacology, School of Medicine, University of Michigan, Ann Arbor, Michigan 48109, United States.
Emily M
EM
Jutkiewicz
†Interdepartmental Program in Medicinal Chemistry, College of Pharmacy, University of Michigan, Ann Arbor, Michigan 48109, United States.|§Department of Medicinal Chemistry, College of Pharmacy, University of Michigan, Ann Arbor, Michigan 48109, United States.
Henry I
HI
Mosberg
D000701:Analgesics, Opioid / Q000097:blood / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D020134:Catalytic Domain; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D008297:Male; D008810:Mice, Inbred C57BL; D015394:Molecular Structure; D009292:Narcotic Antagonists / Q000097:blood / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D059226:Nociceptive Pain / Q000188:drug therapy; D011804:Quinolines / Q000097:blood / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D017465:Receptors, Opioid, delta / Q000037:antagonists & inhibitors* / Q000378:metabolism; D017473:Receptors, Opioid, kappa / Q000378:metabolism; D017450:Receptors, Opioid, mu / Q000819:agonists* / Q000378:metabolism; D013329:Structure-Activity Relationship
D000701:Analgesics, Opioid; D009292:Narcotic Antagonists; D011804:Quinolines; D017465:Receptors, Opioid, delta; D017473:Receptors, Opioid, kappa; D017450:Receptors, Opioid, mu
Opioid; dependence; intraperitoneal; mixed efficacy; tetrahydroquinoline; tolerance