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

Abstract

(+/-)-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)

Long-Acting Fentanyl Analogues: Synthesis and Pharmacology of N-(1-Phenylpyrazolyl)-N-(1-phenylalkyl-4-piperidyl)propanamides

“…These values, which are comparable to those of some of the more potent isomers of ohmefentanyl, eg the oxalate salt of the 2R,3R,4S isomer has a K i =0.013 AE 0.002 nM, 32 do not correlate well with the data obtained in functional assays and analgesic tests. There is, however, a good correlationship between the functional data obtained in isolated tissues and in the antinociceptive tests.…”

“…33 In any case, the absolute K i values should always be considered with certain care since for example, in the case of ohmefentanyl, a potent opioid already mentioned, in which eight optically active isomers are possible, there was controversy in the binding data of the more potent isomers reported by two different groups. 32,34 Nevertheless, a different m-binding study was performed in human recombinant CHO-K1 cells. The K i values in this case were for 3b 1.21 AE 0.11 nM and for 3d 1.04 AE 0.05 nM.…”

Theoretical studies on opioid receptors and ligands. I. Molecular modeling and QSAR studies on the interaction mechanism of fentanyl analogs binding to ?-opioid receptor

“…Then the docked ligands a K i 's were determined on the µ rat brain membrane preparations, and pK i is − log K i (Refs. [10,15,16]); K's were evaluated at the opioid µ binding site in membrane preparations from mouse brain, and pK is − log K (Refs. [11,17]); and ED 50 was estimated with mouse hot plate assay (Refs.…”

“…Satisfied that the 3D structures of ligand-receptor complexes were indeed reasonable, we then per- formed a classical QSAR to explore whether the binding affinities of these analogs could be correlated with the energetic information. The Rothman group [10,15,16] has evaluated the binding affinities (K i 's) for some fentanyl analogs on the µ rat brain membrane preparations (Table I). By using these K i values and employing multiple regression analysis (MRA) [33,34], we calculated the regression equation for the binding affinities, pK i 's (− log K i 's), using the total binding energies, E bind , as the sole descriptor variable.…”

“…Structurally, 2 contains two asymmetric carbon atoms (C3 and C4) and 3 involves three chiral carbon atoms (C3, C4, and C2 ), so they have four and eight enantiomers, respectively. Van Bever [9], Brine et al [10], and Wang et al [11] obtained these enantiomers, and their stereo differences in analgesic potency have been distinguished. The analgesic potency of cis-3-MF is sixfold more potent than that of fentanyl and 1300 times more potent than that of morphine.…”