Molecular Model Of Anticonvulsant And Antidepressant Drug Binding To The Sodium Channel

Voltage-gated Na channels are molecular targets for many classes of drugs, including local anesthetics, antiepileptics (anticonvulsants) and antidepressants. The anticonvulsants phenytoin and carbamazepine have a tricyclic rigid structure and are neutral, in contrast to the positively charged local anesthetics, but they all block the neuronal Na channels with similar affinities. Using a model of the inner pore of the Na channel, which we developed by homology with K channels, we have docked these anticonvulsants (including lamotrigine) with residues identified by mutagenesis as important for their binding. Anticonvulsants are too wide to fit into the modeled closed pore, but they do fit into the open/inactivated pore. The pharmacophore core of anticonvulsants contain amides or similar groups with a high polarity and large partial positive charge on their amines. When these molecules are docked in the pore, the amines participate in amino-aromatic interactions with the side chain of Phe-1764 of DIVS6 (NaV1.2). One aromatic ring of the tricyclic ring interacts with Tyr-1771 of IVS6, and the second aromatic ring is located in the center of the pore, in proximity to domains I-III. It physically occludes the inner pore in contrast to local anesthetics, which do not but create an electrostatic barrier to ion permeation. Hydrophobic interactions with the second aromatic ring also contribute an important energetic component to binding for anticonvulsants, which compensate for the absence of positive charge in their structures. The antidepressants amitriptyline and nortriptyline are structurally similar to carbamazepine, but the side chain at the tricyclic ring is substituted by a tertiary amine. For these an additional cation interaction with Phe-1764 can contribute to their high binding affinity. Supported by NIH HL5-2016.