Synthesis and evaluation of aryl-naloxamide opiate analgesics targeting truncated exon 11-associated μ opioid receptor (MOR-1) splice variants.
作者： Susruta Majumdar , Joan Subrath , Valerie Le Rouzic , Lisa Polikar , Maxim Burgman
DOI: 10.1021/JM300305C
关键词:
摘要: 3-Iodobenzoylnaltrexamide 1 (IBNtxA) is a potent analgesic acting through novel receptor target that lack many side-effects of traditional opiates composed, in part, exon 11-associated truncated six transmembrane domain MOR-1 (6TM/E11) splice variants. To better understand the SAR this drug target, number 4,5-epoxymorphinan analogues were synthesized. Results show importance free 3-phenolic group, phenyl ring at 6 position, an iodine 3′or 4′ position ring, and N-allyl or c-propylmethyl group to maintain high 6TM/E11 affinity activity. 3-Iodobenzoylnaloxamide 15 (IBNalA) with displayed lower δ opioid than its naltrexamine analogue, was 10-fold more morphine, elicited no respiratory depression physical dependence, only limited inhibition gastrointestinal transit. Thus, aryl-naloxamide scaffold can generate sites advantageous side-...
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