Theoretical analysis of the molecular determinants responsible for the K+ channel blocking by aminopyridines

This work presents a theoretical analysis of the molecular determinants responsible for the pharmacological activity (Kf channel blocking) of aminopyridines. Thus, DFT theory at the B3LYP/cc-pVDZ level is applied to a series of active compounds: 2-aminopyridine, 5-aminopyridine, 4-aminopyridine, 3,4-diaminopyridine, and 4-aminoquinoleine. The two forms present in the biological environment, neutral and cationic (protonated), are considered in vacuum as well as in aqueous solution. The results show pyramidal and planar structures for the neutral and cationic forms, respectively. An analysis of the topology of the electron density show that an increase in conjugation between the pyridine ring and the amine group is responsible for the observed planarity of the protonated forms. By computing the Laplacian of the charge density we found the pyridine nitrogen to be the preferred protonation site, as a consequence of a much higher curvature of the charge density field. Also, from three-dimensional (3D) isoLaplacian diagrams a common reactivity pattern is only found in the charged forms. This reactivity pattern implies that interaction with the biological receptor site is mediated by electrostatic interactions and hydrogen bonding. Development of a physical-mathematical model allows identification of the specific relationship of the pharmacological activity index with the affinity for the receptor and the protonation ability. (C) 2001 Elsevier Science B.V. All rights reserved.