Conformational profile of nalorphine by PCILO calculations

Abstract

The substitution of an ally1 group for the methyl group on the nitrogen of morphine changes the pharmacological activity from that of a narcotic agonist to that of a mixed narcotic agonist-antagonist; substitution of an allyl group for the methyl group in oxymorphone changes it from a narcotic agonist to a pure antagonist [ I]. (The molecular structures are depicted in Figure 1.) When we first initiated our quantum chemical investigations on narcotics and narcotic antagonists [2] there was no structural information on the position and conformation of an ally1 group relative to the piperidine moiety in such molecules. Subsequently, at our request Dr. I. Karle graciously determined the crystal structure of naloxone (from a sample which we supplied) [3]. From these atomic coordinates it was possible for us to perform the quantum chemical calculations for naloxone [4-81 at what corresponds to at least one of its most stable minimum energy conformations. We had also calculated similar conformations for nalorphine by both the C N D O /~ and PCILO methods. In our early quantum chemical calculations of nalorphine [9-111 we had used the old crystal structure of morphine [12] and tried various positions of the allyl group relative to the piperidine ring. We noted that there was a discernible sensitivity to the position of the allyl group not only in the calculated total energy but also even in the energy of the highest occupied orbital. While it would have been possible for us to calculate a conformational energy map for nalorphine by the CNDO/2 or INDO methods as we have done for the neuroleptic phenothiazines [4,6,7,[13][14][15], at that time we did not have the sufficient necessary computer time available to this particular praject.The PCILO (Perturbative Configuration Interaction based on Localized Orbitals) method [ 161 developed in the group of Professor B. Pullman has been used most successfully by him and coworkers to calculate the conformational energy maps of a large variety of biological and pharmacological molecules. (Reference [17] presents a comprehensive overview of many of their P C I L .~ results on pharmacological molecules.)Thus, knowing the crystallographic position of the allyl group in naloxone relative to the piperidine moiety, we investigated by PCILO calculations if the same relative position of the allyl group would be the preferred conformation for nalorphine. In the interim a new more accurate crystal structure of morphine was published [18]. We performed the PCILO calculations for nalorphine using Gylbert's crystal structure for morphine replacing the N-methyl group with the allyl group in the same position relative to the piperidine moiety as was found for naloxone [3].Designating the atoms of the allyl side chain of nalorphine (Fig. 1, compound 11) as N--C17-C18=C19r we varied both the angles of N-C17 and CL7-CI8 simultaneously by 30" increments. The resulting map indicated that the position of greatest stability was the one we chose. There was one other small region of stability from 90" to...

Ab initio and nonempirical MODPOT/VRDDO calculations on drugs, carcinogens, suspected teratogens, and biomolecules

“…Ordinarily if there has been a crystal structure determined for a medium or large drug or biomolecule molecule, we initiate our quantum chemical calculations at the molecular geometry as determined in the crystal. Our prior experience [20,21] has indicated that for most molecules of this type, especially ones whose structure is composed primarily of ring skeletons, the major influence on molecular structure is intramolecular rather than crystal packing or intermolecular forces. The molecular structure in the crystal also has to be one of the low-energy permitted conformations.…”

Strategy for computer-generated theoretical and quantum chemical prediction of toxicity and toxicology (and pharmacology in general)

“…We had also used that same concept of meshed pieces of structural conformation of different parts from different molecules to arrive at an initial guess for the structure of nalorphine [33], a narcotic agonist-antagonist (the N-ally1 derivative of morphine). The crystal structure of morphine had been determined [34], as had the crystal structure of naloxone [35].…”

Physicochemical, quantum chemical, and other theoretical studies of the mechanism of action of cns agents: Anesthetics, narcotics and narcotic antagonists, and psychotropic drugs

“…rameters, the INDO procedure (a semirigorous quantum chemical method) seemed only to have been derived and parametrized by Pople [61] for molecules containing first-row atoms. Hence, we extended the INDO formulation by deriving the general INDO equations for d orbitals and obtaining the necessary parameters for secondrow atoms [62].…”