Molecular structure and dynamics of cis(Z)-and trans(E)-flupenthixol and clopenthixol.

The three-dimensional structures and molecular electrostatic potentials of the cis(Z) and trans(E)-isomers of flupenthixol and clopenthixol were examined by computer graphics and molecular mechanical and quantum mechanical calculations, and their internal molecular motions were studied by molecular dynamics simulations in vacuo and in aqueous solution. The simulations demonstrated that both the side chains and the tricyclic ring systems of clopenthixol and flupenthixol are highly flexible. The angle between the two phenyl ring planes varied between 105 and 171 degrees during the simulations in solution. The electrostatic potentials around the 2-substituent were significantly more negative in the trans(E)-isomers than in the cis(Z)-isomers. The stronger negative potentials may weaken electrostatic receptor interactions and, thereby, cause the trans(E)-isomers to be less active than cis(Z)-isomers. Differences both in three-dimensional structure and in electronic structure may cause the difference in pharmacological activity between cis(Z)- and trans(E)-thioxanthenes.