Conformational-dependent basicity of carvedilol Fragment C:: an ab initio study on the primary amine, aminoethoxy-2-methoxy-benzene

Carvedilol produces various physiological effects via multiple modes of action. In mitochondria, it is purported that carvedilol is cardioprotective by acting as a mild uncoupler of oxidative phosphorylation; the mechanism is thought to involve the protonable amino group in its side-chain. This uncoupling subsequently leads to a decrease in production of reactive oxygen species and reduced mitochondrial oxidative stress. In the current work, the carvedilol fragment aminoethoxy-2-methoxybenzene (Fragment Q has been investigated to illustrate the effects of molecular conformation on intrinsic basicity as related to such proton shuttling pathways. It has been previously been shown for carvedilol Fragment B that molecular conformation dictates the energetics of deprotonation. Fragment C is also studied in this context because, as a primary amine which may be deprotonated via three different protons, it provides an ideal structure to elucidate such conformational effects. By calculating the associated energies of deprotonation for each proton, the relative effects of conformation on intrinsic basicity can be determined. The ab initio Hartree-Fock, RHF/3-21G, level of theory was employed for structural analysis and the potential energy hypersurface of Fragment C was computed with geometry optimizations of the conformational minima. Energies of deprotonation were determined with vertical and adiabatic calculations for each proton in each converged minima. Multidimensional conformational analysis of the protonated potential energy hypersurface revealed a total of 24 converged minima out of a possible 81 (approximate to 30% convergence). Conformers with the lowest relative energies possessed a motif consisting of bifurcated hydrogen-bonds forming an eight-membered ring. Hydrogen bond networks forming five-membered rings along with intramolecular dipole-type interactions were also evident. In contrast, protonated conformers with large relative energies were devoid of any significant structural features. Geometry optimization of the deprotonated potential energy hypersurface revealed similar structural features; further, optimization of conformational minima belonging to the deprotonated hypersurface revealed a novel amine-aromatic pi electronic interaction currently under study. In analyzing the derived energetics of deprotonation for the primary amine, it was found that conformers lacking significant stabilizing structural motifs were favored and possessed the lowest energies of deprotonation for Fragment C. The route with the lowest energy of deprotonation (optimized) was via the deprotonation of conformer ag(+)ag(+) which required 238.34 kcal mol(-1). It can thus be concluded that, as previously shown for the secondary amine Fragment B, and now for the primary amine Fragment C, proton shuttling mechanisms involving carvedilol, and amines in general, will favor conformations with minimal intramolecular stabilization. As such, molecular conformation and associated structural features will determine, at least with regards to energetics, the intrinsic basicity of compounds and can be used to describe and predict favored substrate conformations for protonophoretic pathways as that postulated for carvedilol in mitochondria. (C) 2003 Elsevier B.V. All rights reserved.