3-Alkyl ethers of clocinnamox: delayed long-term mu-antagonists with variable mu efficacy.
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 mu-antagonist, MC-CAM has been shown to be a potent partial agonist at mu-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 mu-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 mu-agonist character and was able to substitute for morphine in morphine-dependent monkeys. Interestingly, when this agonist effect abated, 7 displayed long-lasting mu-antagonism. In contrast, 5 displayed little agonist activity in vivo and was characterized as a potent, long-acting mu 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 mu 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 mu efficacy but retaining the long-lasting mu-antagonist effects provide further opportunities for the development of treatment drugs.
School of Chemistry, University of Bristol, Cantock's Close, Bristol, England, BS8 1TS.
S M
SM
Husbands
J
J
Sadd
J H
JH
Broadbear
J H
JH
Woods
J
J
Martin
J R
JR
Traynor
M D
MD
Aceto
E R
ER
Bowman
L S
LS
Harris
J W
JW
Lewis
D000818:Animals; D001921:Brain / Q000378:metabolism; D002934:Cinnamates / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology; D008253:Macaca mulatta; D051379:Mice; D009020:Morphine / Q000633:toxicity; D009022:Morphine Derivatives / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology; D009292:Narcotic Antagonists / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology; D010147:Pain Measurement; D051381:Rats; D017450:Receptors, Opioid, mu / Q000819:agonists / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013375:Substance Withdrawal Syndrome / Q000188:drug therapy
D002934:Cinnamates; D009022:Morphine Derivatives; D009292:Narcotic Antagonists; D017450:Receptors, Opioid, mu; C076806:clocinnamox; D009020:Morphine