Synthesis and biological evaluation of 14-alkoxymorphinans. 20. 14-phenylpropoxymetopon: an extremely powerful analgesic.
The 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, delta), 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).
Schütz
Johannes
J
Department of Pharmaceutical Chemistry, Institute of Pharmacy, University of Innsbruck, Innrain 52a, A-6020 Innsbruck, Austria.
Spetea
Mariana
M
Koch
Martin
M
Aceto
Mario D
MD
Harris
Louis S
LS
Coop
Andrew
A
Schmidhammer
Helmut
H
D000701:Analgesics, Opioid / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D005048:Etorphine / Q000031:analogs & derivatives / Q000494:pharmacology; D006168:Guinea Pigs; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D009019:Morphinans / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D009020:Morphine / Q000494:pharmacology; D009025:Morpholines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D009619:Nociceptors / Q000187:drug effects / Q000502:physiology; D010147:Pain Measurement / Q000187:drug effects; D011869:Radioligand Assay; D051381:Rats; D011930:Reaction Time / Q000187:drug effects / Q000502:physiology; D011957:Receptors, Opioid / Q000378:metabolism; D013329:Structure-Activity Relationship
C478565:14-phenylpropoxymetopon; D000701:Analgesics, Opioid; D009019:Morphinans; D009025:Morpholines; D011957:Receptors, Opioid; D005048:Etorphine; D009020:Morphine