Synthesis and Biological Evaluation of 14-Alkoxymorphinans. 20. 14-Phenylpropoxymetopon: An Extremely Powerful AnalgesicJohannes Schütz, Mariana Spetea, Martin Koch, Mario D. Aceto, Louis S. Harris, Andrew Coop, and Helmut SchmidhammerJ. Med. Chem. 46(19), 4182-4187 (2003)
(
https://www.thevespiary.org/rhodium/Rhodium/pdf/14-phenylpropoxymetopon.pdf)
DOI:
10.1021/jm030878b
AbstractThe synthesis and the biological and pharmacological evaluation of several 14-phenylpropoxy analogues of 14-methoxymetopon are described. Most of the new compounds were nonselective and exhibited binding affinities in the subnanomolar or low nanomolar range at opioid receptors (
mu, kappa, sigma), with 14-phenylpropoxymetopon (PPOM;
7) displaying the highest affinity for all three opioid receptor types. The most striking finding of this study is that the derivatives from the novel series of N-methyl-14-phenylpropoxymorphinans acted as extremely powerful antinociceptives with potencies higher than that of 14-methoxymetopon (
1) and even etorphine. 14-Phenylpropoxymetopon (PPOM;
7) showed considerably increased potency in the in vivo assays in mice (25-fold in the tail-flick assay, 10-fold in the hot-plate assay, and 2.5-fold in the paraphenylquinone writhing test) when compared to etorphine, while it was equipotent to dihydroetorphine in the hot-plate assay and the paraphenylquinone writhing test and ca. twice as potent in the tail-flick assay than this reference compound. The 3-O-alkyl ethers of PPOM, compounds
6 and
8, showed less potency in in vivo assays, but partly surpassed the potency of the 3-OH analogue 14-methoxymetopon (
1).