The role of stacking interactions in clonidine binding

Stacking interactions of the clonidine aromatic ring with that of Phe or Tyr in the α₂-adrenoreceptor and Tyr in the tetrodotoxin-resistant sodium channel pore have been studied. Ab initio quantum-chemical calculations for a model system of two parallel aromatic rings have been performed with the GAMESS software using the 6-31G* basis set in the framework of the second-order Muller-Plesset perturbation theory with full geometry optimization without symmetry constraints. The parallel shifted conformation of two aromatic rings was found to be energetically most favorable. The 2′,6′-chlorination of one of the benzene rings enhances the stacking interaction, somewhat increases the shift of these rings, and possibly improves the hypotensive and analgesic functions of clonidine owing to an increase in the binding energy. The 4-fluorination of the clonidine ring can increase its analgesic effect but practically excludes its hypotensive activity.