Enantiomers of Diastereomeric cis-N-[1-(2-Hydroxy-2-phenylethyl)-3-methyl-4-piperidyl]-N-phenylpropanamides: Synthesis, X-ray Analysis, and Biological Activities

Autor: P. Singh, P. A. Stark, G. A. Brine, Young Liu, Richard B. Rothman, Heng Xu, F. I. Carroll
Rok vydání: 1995
Předmět:
Zdroj: Journal of Medicinal Chemistry. 38:1547-1557
ISSN: 1520-4804
0022-2623
DOI: 10.1021/jm00009a015
Popis: (±)-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 1 H 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 μ site labeled with [ 3 H]DAMGO. In contrast, the four isomers displaced [ 3 H]etorphine in the order 1a, 1b, 1c and 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 (μ), ICI 174864 (δ), and norbinaltorphimine (κ) demonstrated that the effects of 1a were mediated largely by the μ receptor while both δ and κ agonist effects contributed to the actions of 1b and 1c. Isomer 1d acted as a weak μ 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. From this analysis we drew the following conclusions regarding structure: (a) the (3R,4S)-piperidine stereochemistry found in the more potent cis-3-methylfentanyl isomer was required for potent opiate agonist activity; (b) the introduction of a phenylethyl 2-hydroxyl with the S configuration had an enormous impact on this activity as demonstrated by the extraordinary μ agonist properties of 1a and the weak μ agonist/antagonist properties of 1d; and (c) the introduction of a 2-hydroxyl with the R configuration had a much smaller impact on the opiate agonist activity. Finally, our findings demonstrated the importance of the combination of 2-hydroxyl and 3-methyl substituents to the pharmacological properties of the four isomers
Databáze: OpenAIRE
Externí odkaz: