3-Alkyl ethers of clocinnamox

Delayed long-term μ-antagonists with variable μ efficacy

Stephen M. Husbands, John Sadd, Jillian H. Broadbear, James H. Woods, Jason Martin, John R. Traynor, Mario D. Aceto, Edward R. Bowman, Louis S. Harris, John W. Lewis

Research output: Contribution to journalArticle

13 Citations (Scopus)

Abstract

In recent years there has been considerable interest in the relationship between clocinnamox (C-CAM) and its methyl ether methoclocinnamox (MC-CAM). While C-CAM appears to be an insurmountable μ-antagonist, MC-CAM has been shown to be a potent partial agonist at μ-opioid receptors. To further investigate this relationship we prepared other ethers of C-CAM and evaluated these in opioid receptor binding assays and in vivo in mouse antinociceptive assays and in morphine-dependent monkeys. In opioid binding assays, the ethers were generally μ-selective with affinity equivalent to that of C-CAM itself. Although they displayed little or no efficacy in vitro, some of the ethers showed substantial agonist activity in the in vivo antinociceptive tests. TWO of the ethers, the propargyl ether 7 and the cyclopropylmethyl ether 5, were chosen for more detailed analysis in vivo. 7 was shown to have significant μ-agonist character and was able to substitute for morphine in morphine-dependent monkeys. Interestingly, when this agonist effect abated, 7 displayed long-lasting μ-antagonism. In contrast, 5 displayed little agonist activity in vivo and was characterized as a potent, long-acting μ antagonist. Although further work is needed to determine whether metabolism is a crucial factor in determining the pharmacological profile of these ethers, it is clear that 3-O-alkylation is a useful means of varying the μ efficacy displayed by this class of acyl-substituted 14-aminomorphinones. MC- CAM itself has generated considerable interest as a Potential pharmacotherapy for opiate abuse. These analogues with differing μ efficacy but retaining the long-lasting μ-antagonist effects provide further opportunities for the development of treatment drugs.

Original languageEnglish
Pages (from-to)3493-3498
Number of pages6
JournalJournal of Medicinal Chemistry
Volume41
Issue number18
DOIs
Publication statusPublished - 1 Aug 1998

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

Cite this

Husbands, S. M., Sadd, J., Broadbear, J. H., Woods, J. H., Martin, J., Traynor, J. R., ... Lewis, J. W. (1998). 3-Alkyl ethers of clocinnamox: Delayed long-term μ-antagonists with variable μ efficacy. Journal of Medicinal Chemistry, 41(18), 3493-3498. https://doi.org/10.1021/jm9810248

3-Alkyl ethers of clocinnamox : Delayed long-term μ-antagonists with variable μ efficacy. / Husbands, Stephen M.; Sadd, John; Broadbear, Jillian H.; Woods, James H.; Martin, Jason; Traynor, John R.; Aceto, Mario D.; Bowman, Edward R.; Harris, Louis S.; Lewis, John W.

In: Journal of Medicinal Chemistry, Vol. 41, No. 18, 01.08.1998, p. 3493-3498.

Research output: Contribution to journalArticle

Husbands, SM, Sadd, J, Broadbear, JH, Woods, JH, Martin, J, Traynor, JR, Aceto, MD, Bowman, ER, Harris, LS & Lewis, JW 1998, '3-Alkyl ethers of clocinnamox: Delayed long-term μ-antagonists with variable μ efficacy', Journal of Medicinal Chemistry, vol. 41, no. 18, pp. 3493-3498. https://doi.org/10.1021/jm9810248
Husbands, Stephen M. ; Sadd, John ; Broadbear, Jillian H. ; Woods, James H. ; Martin, Jason ; Traynor, John R. ; Aceto, Mario D. ; Bowman, Edward R. ; Harris, Louis S. ; Lewis, John W. / 3-Alkyl ethers of clocinnamox : Delayed long-term μ-antagonists with variable μ efficacy. In: Journal of Medicinal Chemistry. 1998 ; Vol. 41, No. 18. pp. 3493-3498.
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AU - Woods, James H.

AU - Martin, Jason

AU - Traynor, John R.

AU - Aceto, Mario D.

AU - Bowman, Edward R.

AU - Harris, Louis S.

AU - Lewis, John W.

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