Rational Design, Chemical Syntheses, and Biological Evaluations of Peripherally Selective Mu Opioid Receptor Ligands as Potential Opioid Induced Constipation Treatment.

Abstract

Opioid-induced constipation (OIC) is a common adverse effect of opioid analgesics. Peripherally acting μ opioid receptor antagonists (PAMORAs) can be applied in the treatment of OIC without compromising the analgesic effects. NAP, a 6β-N-4-pyridyl-substituted naltrexamine derivative, was previously identified as a potent and selective MOR antagonist mainly acting peripherally but with some CNS effects. Herein, we introduced a highly polar aromatic moiety, for example, a pyrazolyl or imidazolyl ring to decrease CNS MPO scores in order to reduce passive BBB permeability. Four compounds 2, 5, 17, and 19, when administered orally, were able to increase intestinal motility during morphine-induced constipation in the carmine red dye assays. Among them, compound 19 (p.o.) improved GI tract motility by 75% while orally administered NAP and methylnaltrexone showed no significant effects at the same dose. Thus, this compound seemed a promising agent to be further developed as an oral treatment for OIC.

• Authors: Boshi Huang, Mengchu Li, Pornprom Klongkumnuankarn, Rolando E Mendez, James C Gillespie, David L Stevens, William L Dewey, Dana E Selley, Yan Zhang
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 65 Issue 6 Pg. 4991-5003 (03 24 2022) ISSN: 1520-4804 [Electronic] United States
• PMID: 35255683 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Analgesics, Opioid
• Ligands
• Narcotic Antagonists
• Receptors, Opioid, mu
• Naltrexone

Topics

• Analgesics, Opioid (adverse effects)
• Constipation (chemically induced, drug therapy)
• Humans
• Ligands
• Naltrexone (pharmacology, therapeutic use)
• Narcotic Antagonists (pharmacology, therapeutic use)
• Opioid-Induced Constipation
• Receptors, Opioid, mu