The synthesis, biological, and pharmacological evaluation of novel derivatives of cyprodime are described. Their binding affinities at mu, delta, and kappa opioid receptors were evaluated using receptor binding assay. It was observed that the affinity of these compounds was sensitive to the character and length of the substituent in position 4. Further prolongation of the 4-alkoxy group of cyprodime (1) and its 4-butoxy analogue 2 is detrimental for the mu opioid receptor affinity. Introduction of an arylalkoxy group at C-4 does not increase mu affinity in the case of benzyloxy, while a phenylpropoxy group reduces mu affinity. The delta and kappa affinities were also reduced compared to the reference compounds. A significant increase in the affinity at the mu opioid receptors was achieved by introducing a 14-phenylpropoxy group. Increases in the affinity at delta and kappa receptors were also observed. These findings provide further evidence that the nature of the substituent at position 14 has a major impact on the abilities of morphinans to interact with opioid receptors. In the [(35)S]GTPgammaS binding assay, all tested compounds were partial agonists at mu and delta receptors. Compounds 8 and 17 showed antagonism at kappa receptors, while compound 7 exhibited some partial agonist activity at this receptor. The novel derivatives of cyprodime containing a 14-phenylpropoxy group acted as potent antinociceptives. When tested in vivo, compounds 7, 8, and 17 were considerably more potent than morphine, with phenol 7 showing the highest antinociceptive potency (21-fold in the hot plate test, 38-fold in the tail flick test, and 300-fold in the paraphenylquinone writhing test) in mice. Introduction of a 14-phenylpropoxy substituent leads to a profound alteration in the pharmacological profile of this class of compounds.
Journal of Medicinal Chemistry 07/2004; 47(12):3242-7. DOI:10.1021/jm031126k · 5.48 Impact Factor