The frontier orbital phase angles: a theoretical interpretation

A pair of descriptors recently introduced to account for the activity of hallucinogenic phenethylamines has been shown to be a measure of the angles that the nodes of the frontier orbitals make with a reference direction in the molecule, in an approximation to the frontier orbitals of the molecule. The descriptors are referred to as the frontier orbital phase angles Theta(H) and Theta(L), and are calculated with respect to a reference point on the benzene ring. The angle the node of the HOMO makes with the reference atom, measured at the center of the benzene ring is Theta(H) + pi/6, and the angles the nodes in the LUMO make with the same atom are (Theta(L)-pi/6)/2 and (Theta(L)-5 pi/6)/2. The dependence of activity of a drug on Theta(H) and Theta(L), as well as on the energy splitting undergone by the frontier orbitals of benzene in the formation of the drug, is an excellent illustration of the wave mechanical nature of the binding of a drug to its receptor, and should make a valuable contribution to the development of 3D-QSAR programs. (C) 2000 Elsevier Science B.V. All rights reserved.