Structure- and Cation-Dependent Mechanism of the Interaction of Tricyclic Antidepressants with NMDA Receptor According to Molecular Modeling Data

Abstract

Some tricyclic antidepressants (TCA), including amitriptyline (ATL), clomipramine (CLO), and desipramine (DES), are known to be effective for the management of neuropathic pain. It was previously determined that ATL, CLO and DES are capable of voltage-dependent blocking of NMDA receptors of glutamate (NMDAR), which play a key role in the pathogenesis of neuropathic pain. Despite the similar structure of ATL, CLO and DES, efficacy of their interaction with NMDAR varies significantly. In the study presented here, we applied the molecular modeling methods to investigate the mechanism of binding of ATL, CLO and DES to NMDAR and to identify the structural features of the drugs that determine their inhibitory activity against NMDAR. Molecular docking of the studied TCA into the NMDAR channel was performed. The conformational behavior of the obtained complexes in lipid bilayer was simulated by the method of molecular dynamics (MD). A single binding site (upper) for the tertiary amines ATL and CLO and two binding sites (upper and lower) for the secondary amine DES were identified inside the NMDAR channel. The upper and lower binding sites are located along the channel axis at different distances from the extracellular side of the plasmatic membrane (PM). MD simulation revealed that the position of DES in the lower site is stabilized only in the presence of sodium cation inside the NMDAR channel. DES binds more strongly to NMDAR compared to ATL and CLO due to the simultaneous interaction of two hydrogen atoms of its cationic group with the asparagine residues of the ion pore of the receptor. This feature may be responsible for stronger side effects of DES. It has been hypothesized that ATL binds to NMDAR less efficiently compared to DES and CLO due to its lower conformational mobility. The identified features of the structure- and cation-dependent mechanism of interaction between TCA and NMDAR will help in the further development of effective and safe analgesic therapy.