Molecular structure and dynamics of tricyclic antidepressant drugs.

The molecular structure, electrostatic potentials and dynamics of imipramine, chlorimipramine, amitriptyline and nortriptyline were examined by computer graphics, molecular mechanical energy calculations and molecular dynamics simulations, using the AMBER all atom force field. Starting coordinates for amitriptyline and nortriptyline were generated by model building from the crystal structure of imipramine. The structures were refined by molecular mechanical energy minimization, and used as starting points for molecular dynamics simulations in vacuo and in aqueous solution. The simulations demonstrated considerable flexibility of the molecules, both in the side chain and in the ring system, where the angle between the phenyl rings varied between 90 degrees and 168 degrees. The most frequently observed conformations of imipramine, chlorimipramine and nortriptyline during the simulations had the side chain folded above one of the phenyl rings, while amitriptyline showed both folded and extended side chain conformations during the simulations. The results may provide increased understanding of the molecular recognition and specificity of tricyclic antidepressant drugs in interaction with neurotransmitter receptor molecules.