Synthesis and evaluation of aryl-naloxamide opiate analgesics targeting truncated exon 11-associated μ opioid receptor (MOR-1) splice variants Journal Article
| Authors: | Majumdar, S.; Subrath, J.; Le Rouzic, V.; Polikar, L.; Burgman, M.; Nagakura, K.; Ocampo, J.; Haselton, N.; Pasternak, A. R.; Grinnell, S.; Pan, Y. X.; Pasternak, G. W. |
| Article Title: | Synthesis and evaluation of aryl-naloxamide opiate analgesics targeting truncated exon 11-associated μ opioid receptor (MOR-1) splice variants |
| Abstract: | 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′or 4′ 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 δ 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. © 2012 American Chemical Society. |
| Keywords: | controlled study; unclassified drug; exon; nonhuman; drug targeting; mouse; animal experiment; drug potency; drug screening; drug selectivity; drug synthesis; structure activity relation; drug receptor binding; receptor affinity; morphine; respiration depression; drug binding site; mu opiate receptor; lipophilicity; allyl compound; tail flick test; stereochemistry; naloxone; benzene derivative; polycyclic aromatic hydrocarbon derivative; naltrexone; analgesic activity; gastrointestinal transit; opiate addiction; amide; phenol derivative; delta opiate receptor; oxymorphone; kappa opiate receptor; opiate derivative; levallorphan; 17 allyl 3,14beta dihydroxy 4,5alpha epoxy 6beta [(3' iodo)benzamido]morphinan; 3 iodobenzoylnatrexamide; 4,5 epoxymorphinan derivative; morphinan derivative; naltrexamine derivative |
| Journal Title: | Journal of Medicinal Chemistry |
| Volume: | 55 |
| Issue: | 14 |
| ISSN: | 0022-2623 |
| Publisher: | American Chemical Society |
| Date Published: | 2012-07-26 |
| Start Page: | 6352 |
| End Page: | 6362 |
| Language: | English |
| DOI: | 10.1021/jm300305c |
| PROVIDER: | scopus |
| PMCID: | PMC3412067 |
| PUBMED: | 22734622 |
| DOI/URL: | |
| Notes: | --- - "Export Date: 4 September 2012" - "CODEN: JMCMA" - "Source: Scopus" |
