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

Opioid-induced constipation (OIC) is a common adverse effect of opioid analgesics. Peripherally acting mu opioidreceptor antagonists (PAMORAs) can be applied in the treatment ofOIC without compromising the analgesic effects. NAP, a 6 beta-N-4-pyridyl-substituted naltrexamine derivative, was previously identified asa potent and selective MOR antagonist mainly acting peripherally butwith some CNS effects. Herein, we introduced a highly polar aromaticmoiety, for example, a pyrazolyl or imidazolyl ring to decrease CNSMPO scores in order to reduce passive BBB permeability. Fourcompounds2,5,17, and19, when administered orally, were able toincrease intestinal motility during morphine-induced constipation inthe carmine red dye assays. Among them, compound19(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