ALBERT

Notes: We formulated a pharmacological-physiological systems analysis and control theory based on interactive neuronal feedback loops (the effects of endogenous neurochemical diseases and exogenous psychotropic and other CNS drugs on neurotransmitter synthesis and release, reuptake, and metabolism) for normal, abnormal, and catastrophic situations.We were concerned primarily with the problems of stability or instability which might lead the system to exhibit catastrophic behavior. We set up the systems diagrams for the neurotransmitter systems and in that single framework were able to describe endogenous neurochemical disorders, the effect their drug treatment modalities had on the dynamic neurochemical balance, the effect psychotropic or other CNS drugs such as narcotics and narcotic antagonists had on neurotransmitter balance, and the interactive effect that multiple drug administration would have on neurotransmitter balance. Endogenous neurochemical disorders such as schizophrenia, Parkinsonism, depression, and mania should show up mathematically either as overly damped solutions if there is too little normal neurotransmitter or as catastrophically divergent instabilities if there is too much normal neurotransmitter. Improper mixed drug therapies, as well as the devastating effect of eating foods such as cheese (which contains sympathomimetic amines which potentiate the release of catecholamines from the presynaptic nerve endings) while on MAOI therapy also show up as mathematical, usually catastrophic, instabilities. We also indicated how this systems analysis and control theory could be put on small interactive computer terminals for use in clinical management and proper drug therapy of patients with neurochemical disorders.

Notes: The electrostatic potential V(r) arising from the ab initio LCAO-MO-SCF wave functions of chlorpromazine (CPZ) and promazine (PZ) has been calculated and discussed. In this approximation, the most probable sites of attack and reaction paths of electrophilic reagents are pointed out and compared. The analysis of V(r) shows that the phenothiazine group has strong nucleophilic properties which are influenced by the phenothiazine substituent and that the electrostatic reactivity of CPZ and PZ is decidedly different near the phenothiazine substituent and similar near the side chain N atom. The dependence of V(r) on the accuracy of the wave function has also been discussed by comparing some ab initio results on pyrrole, pyrazole, and imidazole obtained with a large basis set with an ab initio minimum basis set and with CNDO calculations.

Notes: Ab initio MODPOT/VRDDO/MERGE calculations were carried out on carcinogenic 3-methylcholanthrene (3-MCA) and its metabolites. The results for 3-MCA were compared to our earlier similar calculations for carcinogenic benzo(a)pyrene (BP). Both compounds 3-MCA and BP are carcinogenic and are metabolically activated by similar mechanisms but in different positions. Both the calculated wave functions for 3-MCA and BP and the electrostatic molecular potential contour maps generated from these wave functions correctly reflect the similarity of mechanisms of metabolic activation and the differences in position. Our calculated results both for BP and for 3-MCA reflect accurately their experimentally observed behavior. Thus this combination of theoretical techniques can be used with confidence to describe the behavior of the polycyclic aromatic hydrocarbons (PAH's) and their metabolites. The ab initio MODPOT/VRDDO method incorporates two very desirable options into our fast ab initio Gaussian programs: MODPOT-ab initio effective core model potentials - and a charge-conserving integral prescreening approximation which we named VRDDO (variable retention of diatomic differential overlap). For orbital energies and population analysis the MODPOT/VRDDO results agree to essentially three decimal places with completely ab initio calculations using the same valence atomic basis set. For this series of very closely related congeners our recent MERGE technique which allows reuse of integrals from a common skeletal fragment was used. The ab initio MODPOT/VRDDO/MERGE calculations were carried out for 3-MCA, 3-MCA oxides, 3-MCA dihydrodiols, and 3-MCA dihydrodiolepoxides. The metabolites investigated were 3-MCA 9,10-oxide; 3-MCA 7,8-oxide; 3-MCA 9,10-dihydrodiol [trans(axial, axial); trans(equatorial, equatorial); cis(axial, equatorial); cis(equatorial, axial)]; and 3-MCA 9,10-dihydrodiol-7,8-epoxide [for both conformations A and B of the dihydrodiol and for all stereoisomers of the dihydrodiolepoxides relative to below and above the plane: ααα, and ααβ αβα αββ βαα βαβ ββα and βββ (most stable)]. Calculations were also carried out for opening of the C7—O—C8 epoxide ring both towards C7 and C8 for the most stable isomer Aβββ (above the ring). Opening the epoxide ring between C7 and O leads to a more stable intermediate than opening the epoxide ring between C8 and O. Again, however, as with opening the epoxide ring in BP 7,8-dihydrodiol-9,10-epoxide there is no buildup of positive charge on C7 in the 3-MCA metabolites as postulated by some cancer researchers, but rather the C7 becomes slightly more negative. Nor is there a buildup of negative charge on the O atom, but rather it becomes slightly more positive. As the epoxide ring is opened further than 90° for the O—C7—C8 or O—C8—C7 angles, there appears to be a possible mixing of configurations that is being investigated further.

Notes: Ab-initio MODPOT/VRDDO/MERGE SCF calculations were carried out on 2,6-dimethyl-N-nitroso morpholine and on four isomers of α-hydroxy substituted derivatives. The NNO bond angle is found to be 1135°, in agreement with that observed in dimethyl nitrosamine. The two methyl groups are found to be most stable in the equatorial position. The axial position is found to be the most stable orientation for the α-hydroxy group in both the syn and the anti isomers. This is in agreement with the observed axial orientation of straight chain alkyl substituents at the α position in N-nitroso piperidine. An investigation was made on the effects of internal rotation in the parent compound. A 90° rotation about the N—N bond raises the energy ∼.0526 a.u. or ∼33 kcal/mol. In the 90° orientation, population analysis shows a decrease of ∼0.1 e in the gross atomic population (GAP) of the nitroso oxygen and in the total overlap population for the N—N bond. There is a corresponding increase of ∼0.05 e in the GAP on the amino nitrogen. The GAP on other heavy atoms and overlap in other bonds show little effect from internal rotation of the nitroso group. Electrostatic molecular potential energy contour maps indicate differences as a function of conformation.

Notes: Steady-state conductivity and dielectric measurements in the range of 10-5 Hz to 33 GHz are reported for bovine serum albumin and lysozyme as a function of hydration and NaCl content. The electrical properties are understandable in terms of the existence of charge carriers whose hopping-type transport process is directly influenced by the nature of the protein-water interaction. These mobile charges are considered to be protons originating from ionizable carboxylic groups.

Notes: Theoretical and quantum chemical prediction of toxicity and toxicology is even more challenging than prediction of pharmacology, which is usually a one-stage event at a target site. For toxicity and toxicology, the concept of the “toxic triggering event” was developed which then leads to the cascade of subsequent physiological events. The strategy for computer-generated predictions in this area includes as the major components chemical automated substructure and “toxicophore” identification by powerful chemical substructure searching techniques developed in Europe, geometry optimizations (desirably by ab-initio intramolecular atom class-atom class pair-pair and three-body potentials), quantum chemical calculations (desirably ab-initio, incorporating optimal strategies for such computations on large molecules) on both the toxicant and its metabolites (the structures of which were generated by computer-assisted tracing of metabolic pathways), generation of the three-dimensional electrostatic molecular potential contour maps around the toxicants and their metabolites and matching of these by reverse image holography for new compounds whose toxicity has not yet been tested experimentally against those with a known toxic mechanism, matching of intermolecular interaction maps of untested compounds with known toxicants combined with matching observed physiologic signs and symptoms with “toxic triggering events” and specific pathologies, and using the concepts of systems analysis and control theory and catastrophe theory to track both the dynamic balance of endogenous biomolecules and interactions with these biomolecules. The necessary program modules are described, and the necessary data bases (both theoretical and physiological) are identified along with the form in which they may be used most expeditiously.

Notes: In the propagation step of the cationic polymerization, oxetane reacts with the protonated oxetane formed in the initiation step, with concomitant ring opening of the protonated oxetane. To describe properly bond making or bond breaking, it is necessary to use MC-SCF or CI calculations. We have carried out ab initio MODPOT/VRDDO MRD-CI calculations (by the multireference double excitation-configuration interaction technique of Buenker and Peyerimhoff into which we have also meshed a number of desirable computational options for ab initio calculations on large molecules). The CI calculations were carried out on strictly orthogonalized localized occupied and virtual orbitals in the reaction region, with the remainder of the occupied molecular orbitals being folded into an effective CI Hamiltonian. The calculated potential energy surfaces indicate that a preferred pathway for this reaction resembles an SN2 reaction with the oxygen of the oxetane attacking linearly along the C4—O direction of the protonated oxetane and inversion of the hydrogens around the C4 atom.