| Literature DB >> 23116124 |
Yunyun Yuan1, Orgil Elbegdorj, Jianyang Chen, Shashidhar K Akubathini, Feng Zhang, David L Stevens, Irina O Beletskaya, Krista L Scoggins, Zhenxian Zhang, Phillip M Gerk, Dana E Selley, Hamid I Akbarali, William L Dewey, Yan Zhang.
Abstract
Peripheral selective μ opioid receptor (MOR) antagonists could alleviate the symptoms of opioid-induced constipation (OIC) without compromising the analgesic effect of opioids. However, a variety of adverse effects were associated with them, partially due to their relatively low MOR selectivity. NAP, a 6β-N-4'-pyridyl substituted naltrexamine derivative, was identified previously as a potent and highly selective MOR antagonist mainly acting within the peripheral nervous system. The noticeable diarrhea associated with it prompted the design and synthesis of its analogues in order to study its structure-activity relationship. Among them, compound 8 showed improved pharmacological profiles compared to the original lead, acting mainly at peripheral while increasing the intestinal motility in morphine-pelleted mice (ED(50) = 0.03 mg/kg). The slight decrease of the ED(50) compared to the original lead was well compensated by the unobserved adverse effect. Hence, this compound seems to be a more promising lead to develop novel therapeutic agents toward OIC.Entities:
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Year: 2012 PMID： 23116124 PMCID： PMC3527108 DOI： 10.1021/jm301247n
Source DB: PubMed Journal: J Med Chem ISSN： 0022-2623 Impact factor: 7.446