Synthesis and Evaluation of Aryl-Naloxamide Opiate Analgesics Targeting Truncated Exon 11-Associated 渭 Opioid Receptor (MOR-1) Splice Variants

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• 作者：Susruta Majumdar ; Joan Subrath ; Valerie Le Rouzic ; Lisa Polikar ; Maxim Burgman ; Kuni Nagakura ; Julie Ocampo ; Nathan Haselton ; Anna R. Pasternak ; Steven Grinnell ; Ying-Xian Pan ; Gavril W. Pasternak
• 刊名：Journal of Medicinal Chemistry
• 出版年：2012
• 出版时间：July 26, 2012
• 年：2012
• 卷：55
• 期：14
• 页码：6352-6362
• 全文大小：350K
• 年卷期：v.55,no.14(July 26, 2012)
• ISSN：1520-4804

文摘

3-Iodobenzoylnaltrexamide 1 (IBNtxA) is a potent analgesic acting through a novel receptor target that lack many side-effects of traditional opiates composed, in part, of exon 11-associated truncated six transmembrane domain MOR-1 (6TM/E11) splice variants. To better understand the SAR of this drug target, a number of 4,5-epoxymorphinan analogues were synthesized. Results show the importance of a free 3-phenolic group, a phenyl ring at the 6 position, an iodine at the 3鈥瞣r 4鈥?position of the phenyl ring, and an N-allyl or c-propylmethyl group to maintain high 6TM/E11 affinity and activity. 3-Iodobenzoylnaloxamide 15 (IBNalA) with a N-allyl group displayed lower 未 opioid receptor affinity than its naltrexamine analogue, was 10-fold more potent an analgesic than morphine, elicited no respiratory depression or physical dependence, and only limited inhibition of gastrointestinal transit. Thus, the aryl-naloxamide scaffold can generate a potent analgesic acting through the 6TM/E11 sites with advantageous side-effect profile and greater selectivity.