Geometrical correspondence between phenazocine and the enkephalins

Calculations have been performed on phenazocine using Allinger's MM2 (molecular mechanics II) program with full energy minimization. The N-phenethyl group was found to have considerable flexibility with a number of low-energy conformers. The best N-phenethyl axial conformer was 1.6 kcal/mol higher in energy than the best equatorial one. Calculations were also performed on the beta isomer of phenazocine with the result that the energy difference between the best equatorial and axial conformers rose to a substantial 4.6 kcal/mol. The hypothesis that opiate agonism requires an N substituent in the axial position does not appear to be consistent with the increased potency of beta isomers in which axial N substituents are thermodynamically more unstable. Comparisons have also been made between the low-energy conformers of phenazocine and those that have been observed or proposed for the enkephalins. One conformation of the tyrosine portion of the enkephalins that was observed by X-ray crystallography by Karle et al. was found to be a good fit to morphine-like opiates. The backbone conformer suggested by Gorin et al. was found to be the best fit to the two phenyl rings of phenazocine.