Molecular analysis of hexahydro-1H-indeno[1,2-b]pyridines: potential antidepressants

Biological tests indicate hexahydro-1H-indeno[1,2-b]pyridines to be potential human antidepressants with additional stimulating properties. Two diastereomeric series with H4a,H5-trans,H4a,H9b-cis and H4a,H5-cis,H4a,H9b-cis configurations have been tested biologically. The results revealed that the H4a,H5-cis,H4a,H9b-cis series and the ortho-substituted 5-phenyl H4a,H5-trans,H4a,H9b-cis compounds lack activity. Neither the conformation with lowest potential energy nor any other electron-derived parameter correlate with these data. The only relevant difference between the active and the inactive compounds detected thus far is the rotational barrier of the phenyl in the 5-position. The conclusion was reached that certain conformations, which do not resemble those of lowest potential energy, cannot be adopted by the inactive compounds. Therefore, the interaction of the drug with the binding site, responsible for its biological activity, appears to be governed by a dynamic process. This process is characterized by a transformation of the conformation of lowest potential energy to one with an energy content above the minimum.