Department of Medicinal Chemistry, School of Pharmacy, Virginia Commonwealth University, 800 East Leigh Street, Richmond, Virginia 23298, United States.
Department of Pharmacology and Toxicology, School of Medicine, Virginia Commonwealth University, 410 North 12th Street, Richmond, Virginia 23298, United States.
J Med Chem. 2022 Mar 24;65(6):4991-5003. doi: 10.1021/acs.jmedchem.1c02185. Epub 2022 Mar 8.
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 , , , and , when administered orally, were able to increase intestinal motility during morphine-induced constipation in the carmine red dye assays. Among them, compound (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.
阿片类药物引起的便秘（OIC）是阿片类镇痛药的常见不良反应。外周作用μ阿片受体拮抗剂（PAMORAs）可用于治疗 OIC，而不会影响镇痛效果。NAP 是一种 6β-N-4-吡啶基取代的纳曲胺衍生物，先前被鉴定为一种强效和选择性 MOR 拮抗剂，主要作用于外周，但也有一些中枢神经系统作用。在此，我们引入了一个高度极性的芳基部分，例如吡唑基或咪唑基环，以降低 CNS MPO 评分，从而降低被动 BBB 通透性。四种化合物 、 、 和 ，当口服给予时，能够在阿片类药物引起的便秘的胭脂红染料试验中增加肠道蠕动。其中，化合物 （p.o.）改善 GI 道动力提高了 75%，而口服给予 NAP 和甲基纳曲酮在相同剂量下没有显著效果。因此，该化合物似乎是一种有前途的药物，可进一步开发为治疗 OIC 的口服药物。
