Structure-activity relations in analgesics based on 4-anilinopiperidine

Abstract

The synthesis of some 1-alkyl and l-aralkyl-4-(N-phenylpropionamid0)piperidines and related derivatives is described and the hot-plate activities in mice of these compounds reported. Activity variations among 1-methyl, 1-benzyl, and 1-phenethyl derivatives resemble those of corresponding open-chain anilide rather than 4-phenyl-piperidine analgesics. Infrared and nmr data show the two nitrogen atoms of the 4-anilinopiperidine derivatives to be further apart than those of open-chain anilides in their respective preferred conformations ; these results, together with the extreme potency difference between the N-phenethyl derivatives diampromide and fentanyl, show that the two classes are best regarded as mutually distinct types of analgesic.

Development of a conformational search strategy for flexible ligands: A study of the potent ?-selective opioid analgesic fentanyl

“…This conclusion is in clear contrast with the available spectroscopic data, which predict the chair equatorial-equatorial to be the most stable conformation in solution and seem to rule out any significant contribution from the hydrogen-bonded boat conformation [9]. To address this discrepancy, it was necessary to investigate the effect of the solvent environment on the energy ranking of the different conformers.…”

“…Information about the probable solution conformation of fentanyl in chloroform has been obtained through 1H NMR and IR spectroscopy [9]. According to the 1H NMR spectroscopic data, confirmed by a recent 13C NMR study of fentanyl and analogs [10], the more favored conformers of 1 and the 4-anilidopiperidine derivatives are also predicted to be piperidine chairs with equatorial phenylpropanamide groups, consistent with the X-ray studies.…”

“…The results of the isolated state computations favoring the boat clearly show a discrepancy with solution spectroscopic data [9,10]. Also, pharmacological data available for a series of fentanyl analogs, in which the piperidine ring is conformationally restricted [30,31], seem to indicate that the piperidine ring is in the chair rather than the boat conformation in the active form of fentanyl.…”

“…To address this discrepancy, it was necessary to investigate the effect of the solvent environment on the energy ranking of the different conformers. Both the 1H NMR and the IR spectra of fentanyl were recorded in chloroform [9]. Thus, the effect of this solvent was simulated by changing the value of the dielectric constant e from 1 to 4.8 (dielectric constant of chloroform at 20°C [28]) and reoptimizing the structures using CHARMm.…”

Fentanyl Synthetic Methodology: A Comparative Study

“…The starting material, 12 (25 g,/$87.10. Aldrich) can be prepared from phenethylamine (8), and methyl acrylate (9) in methanol via the intermediate diester, 10. The hydrolysis yielded the desired 4-piperidone, 12 in good yield (Scheme 2).…”