ENANTIOMERS OF DIASTEREOMERIC LETHYL)-3-METHYL-4-PIPERIDYL]-N-PHENYLPROPANAMIDES - SYNTHESIS, X-RAY-ANALYSIS, AND BIOLOGICAL-ACTIVITIES

ylethyl)-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 o f optical isomers. These four stereoisomers were prepared from optical ly active intermediates of known absolute configuration by procedures which had no effect on the configurations of the piperidine 3- and 4-c arbons. The configuration of the phenylethyl 2-carbon in the final pro ducts was determined by X-ray analysis of (2S,3S,4R)-1d. A H-1 NMR com parison of the final products to ohmefentanyl established that the rac emic 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. Th e binding data revealed that isomers 1b and 1c had the highest affinit y and selectivity for the mu site labeled with [H-3]DAMGO. In contrast , the four isomers displaced [H-3]etorphine in the order 1a approximat e to 1b > 1c approximate to 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 1 c. 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 rhes us monkey single dose suppression study. From the latter study the pot ency of 1a was estimated to be 20 000-50 000 times that of morphine, m aking this isomer one of the most potent opiates known. In the rhesus monkey study, isomer 1d failed to substitute for morphine and seemed t o exacerbate withdrawal at doses of 0.6, 3.0, and 6.0 mg/kg. On the ba sis 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 vi vo. Using the optical isomers of cis-3-methylfentanyl as reference com pounds, we analyzed the effects on the pharmacological activities of i ntroducing a phenylethyl 2-hydroxyl group into the molecule. From this analysis we drew the following conclusions regarding structure: (a) t he (3R,4S)-piperidine stereochemistry found in the more potent cis-3-m ethylfentanyl isomer was required for potent opiate agonist activity; (b) the introduction of a phenylethyl 2-hydroxyl with the S configurat ion had an enormous impact on this activity as demonstrated by the ext raordinary mu agonist properties of 1a and the weak mu agonist/antagon ist properties of 1d; and (c) the introduction of a 2-hydroxyl with th e R configuration had a much smaller impact on the opiate agonist acti vity. Finally, our findings demonstrated the importance of the combina tion of 2-hydroxyl and 3-methyl substituents to the pharmacological pr operties of the four isomers.