Gas phase conformational basicity of carvedilol fragment B, 2(S)-1-(ethylamonium)propane-2-ol: An ab initio study on a protonophoretic of oxidative phosphorylation uncoupling

Carvedilol is cardiovascular drug of proven efficacy. It is believed that carvedilol exerts cardio-protective effects by acting as a mild uncoupler of mitochondrial oxidative phosphorylation, thereby protecting mitochondria from oxidative stress and preserving proper bioenergetics and cardiac function. This uncoupling occurs via a proton-shuttling mechanism involving the amino group of carvedilol's side-chain. However, the molecular details of carvedilol's proton affinity have not yet been completely worked out, especially with regards to the attributes of molecular conformation. In the present study, the full conformational basicity of a fragment of carvedilol, 2(S)-1-(ethylamonium)propane-2-ol (Fragment B), is presented to illustrate the protonophoretic character of carvedilol. Full gas phase geometry optimizations were performed at the ab initio, RHF/3-21G, level of theory for the entire potential energy hypersurface (PEHS) of Fragment B. Subsequently, since deprotonation can occur via two different protons, a two-prong methodology was applied to calculate vertical and adiabatic energies of deprotonation. A total of 18 out of a possible 81 minima converged and the dominant characteristic in all protonated and deprotonated conformers was a gauche plus effect in the rotation about the C-OH bond at the Fragment B stereocentre. Optimized energies of deprotonation ranged from 245 to 262 kcal mol-1 while protons involved in internal hydrogen bonding required an extra 6-8 kcal mol-1 for deprotonation compared to protons that were oriented away from the backbone structure. The overall trend indicates that conformers devoid of significant stabilization interactions possessed lower energies of deprotonation; in other words, as the relative conformer energy increased, vertical and adiabatic energies of deprotonation tended to decrease. Thus, extrapolating to carvedilol and the proton transfer mechanism involved in oxidative phosphorylation uncoupling, events of deprotonation will favour molecular conformations with minimal intramolecular stabilization and with higher relative energies