Design, Synthesis, and Biological Evaluation of 17-Cyclopropylmethyl-3,14尾-dihydroxy-4,5伪-epoxy-6尾-[(4鈥?pyridyl)carboxamido]morphinan Derivatives as Peripheral Selective 渭 Opioid Receptor Agents

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• 作者：Yunyun Yuan ; 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
• 刊名：Journal of Medicinal Chemistry
• 出版年：2012
• 出版时间：November 26, 2012
• 年：2012
• 卷：55
• 期：22
• 页码：10118-10129
• 全文大小：475K
• 年卷期：v.55,no.22(November 26, 2012)
• ISSN：1520-4804

文摘

Peripheral selective 渭 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 6尾-N-4鈥?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鈥揳ctivity 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 (ED₅₀ = 0.03 mg/kg). The slight decrease of the ED₅₀ 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.