Molecular determinants for drug–receptor interactions. Part 13. X-Ray molecular structure of naltrexone malonate and quantum chemical studies of the conformations of the pure narcotic antagonists naloxone and naltrexone

Abstract

The X-ray molecular structure of naltrexone malonate [(C₂₀H₂₄NO₄)⁺(C₃H₃O₄)^–] was determined. In the T-shape molecule, the D and E rings adopt a chair conformation. Ring B is enveloped (C_s). The configuration of the N-cyclopropylmethyl group is equatorial. The preferred conformations and the energetics of the conformational processes of naloxone and naltrexone, as non-protonated (NLX and NTRX) and protonated (NLXH⁺ and NTRXH⁺) species, were studied using semiempirical MO calculations of the AM-1 type. The solid-state conformations about the N-substituent groups were not retained in calculations for isolated molecules. The NTRXH⁺ species was more conformationally restricted than was NLXH⁺ about the N–C(17) and, especially, C(17)–C(18) bonds. The conformational isoenergy maps calculated for NLX and NTRX showed that the energy barriers were lower, and that the minima zones were larger and shallower with respect to the cationic species. The present findings provided some insights into the possible conformation–activity requirements for µ-pure opioid antagonists.