morphine and clocinnamox

In recent years there has been substantial interest in the 14-aminodihydromorphinone derivatives methoclocinnamox (MC-CAM) and clocinnamox (C-CAM). To investigate the importance of the cinnamoyl ring substituent, a series of analogues have been prepared with chloro, methyl, and nitro substituents in the 2' and 4' positions. Despite some discrepancies between the in vitro and in vivo data, a clear SAR could be observed where the 2'-chloro and 2'-methyl ligands consistently displayed higher efficacy than their 4'-substituted analogues. The new series also followed the well-established SAR that 17-methyl ligands have greater efficacy at the mu opioid receptor than their 17-cyclopropylmethyl counterparts.

Topics: Cinnamates; Codeine; Drug Design; Ligands; Molecular Structure; Morphine Derivatives; Receptors, Opioid, mu; Stereoisomerism; Structure-Activity Relationship

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.

Topics: Animals; Brain; Cinnamates; Macaca mulatta; Mice; Morphine; Morphine Derivatives; Narcotic Antagonists; Pain Measurement; Rats; Receptors, Opioid, mu; Substance Withdrawal Syndrome