Enantiomers of diastereomeric cis-N-[1-(2-hydroxy-2-phenylethyl)- 3-methyl-4-piperidyl]-N-phenylpropanamides: synthesis, X-ray analysis, and biological activities.
(+/-)-cis-N-[1-(2-Hydroxy-2-phenylethyl)-3-methyl-4-piperidyl]-N- phenylpropanamide (1) is a mixture of four stereoisomers [(2S,3R,4S)-1a, (2R,3R,4S)-1b, (2R,3S,4R)-1c, and (2S,3S,4R)-1d], which together constitute two diastereoisomeric pairs of optical isomers. These four stereoisomers were prepared from optically active intermediates of known absolute configuration by procedures which had no effect on the configurations of the piperidine 3- and 4-carbons. The configuration of the phenylethyl 2-carbon in the final products was determined by X-ray analysis of (2S,3S,4R)-1d. A 1H NMR comparison of the final products to ohmefentanyl established that the racemic pair previously known as ohmefentanyl was a mixture of (2S,3R,4S)-1a and (2R,3S,4R)-1c. The individual activities of 1a, 1b, 1c, and 1d were evaluated in a variety of binding and pharmacological assays. The binding data revealed that isomers 1b and 1c had the highest affinity and selectivity for the mu site labeled with [3H]DAMGO. In contrast, the four isomers displaced [3H]etorphine in the order 1a approximately 1b > 1c approximately 1d. Evaluation of the four isomers on the mouse vas deferens (MVD) preparation revealed a potency order of 1a > 1b > 1c > 1d with concentrations of 1a and 1b in the femtomolar range causing inhibition. Experiments using the antagonists naltrexone (mu), ICI 174864 (delta), and norbinaltorphimine (kappa) demonstrated that the effects of 1a were mediated largely by the mu receptor while both delta and kappa agonist effects contributed to the actions of 1b and 1c. Isomer 1d acted as a weak mu antagonist in the MVD preparation. The same potency order was observed in a mouse analgesic assay and a rhesus monkey single dose suppression study. From the latter study the potency of 1a was estimated to be 20,000-50,000 times that of morphine, making this isomer one of the most potent opiates known. In the rhesus monkey study, isomer 1d failed to substitute for morphine and seemed to exacerbate withdrawal at doses of 0.6, 3.0, and 6.0 mg/kg. On the basis of the mouse data, isomer 1a was 21,000 times more potent than 1d, whereas isomers 1b and 1c were similar in their opiate activity in vivo. Using the optical isomers of cis-3-methylfentanyl as reference compounds, we analyzed the effects on the pharmacological activities of introducing a phenylethyl 2-hydroxyl group into the molecule.(ABSTRACT TRUNCATED AT 400 WORDS)
Brine
G A
GA
Research Triangle Institute, Research Triangle Park, North Carolina 27709, USA.
Stark
P A
PA
Liu
Y
Y
Carroll
F I
FI
Singh
P
P
Xu
H
H
Rothman
R B
RB
D000700:Analgesics / Q000737:chemistry* / Q000494:pharmacology; D000818:Animals; D018360:Crystallography, X-Ray; D005283:Fentanyl / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D008253:Macaca mulatta; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D051381:Rats; D013237:Stereoisomerism
D000700:Analgesics; C037016:F 7302; D005283:Fentanyl