Part 1. Design, synthesis, and structure-activity studies of molecules with activity at non-NMDA glutamate receptors: Hydroxyphenylalanines, quinoxalinediones and related molecules. Part 2. Computational studies on the interaction of the dopamine amino gr

摘要

A series of mono- and dinitro- ortho- and meta-tyrosines was prepared, and their activity compared with willardiine (WDN), 5-nitro- scDL-willardiine (NO2WDN), AMPA (;Ab initio quantum mechanical calculations were performed for the acetate anion and ethylammonium and ethyltrimethylammonium cations. Basis sets of modest size (e.g. 6-31G** or DZPP) appeared to give adequate representation of geometries, but the addition of diffuse functions substantially lowered the energies of the HOMO for acetate and the LUMO for the cations. Proton affinities were calculated for formate, acetate, formic acid, acetic acid, methylamine, methanol, and ethanol using the DZPP basis at the Hartree-Fock (HF) and HF/MP2 level, and also using density functional theory (DFT). The HF/MP2 calculations gave good agreement with experiment in most cases. DFT calculations also reproduced experimental values provided that non-local spin density (NLSD, density gradient) corrections were applied. DFT geometries using the local spin density (LSD) treatment were in excellent agreement with HF/MP2 geometries except for C-H, N-H, and O-H bond lengths, which were overestimated. Complexes of formic acid and methylamine were studied as models of dopamine: dopamine receptor interactions. DFT using the LSD approximation gave hydrogen bonds which were shorter and considerably stronger than those obtained with HF/MP2 methods and basis sets up to 6-311++G**. NLSD corrections brought the bond energies to within a few kcal/mol of the HF/MP2 values, but we could not yet perform geometry optimizations using NLSD methodology.