Neuroleptics and beta-carbolines displace (3H)Imipramine from its binding sites in human and rat tissues

Most investigations dealing with the pharmacological characterization of (3H)imipramine binding sites focus on tricyclic antidepressants (TCA). This approach seemed to be justified since imipramine belongs to that chemical group. Langer and coworkers, however, introduced a tetrahydro-beta-carboline (TH beta C) as a possible endogenous ligand. Thus, the high affinity of imipramine towards the binding sites might not be due to its special chemical structure but due to its tricyclic nature. In the present paper the structure-activity-relationships of neuroleptics and beta-carbolines were investigated and compared with that of tricyclic antidepressants. Among the tricyclic neuroleptics those with an electron attracting substituent (-Cl) exerted highest affinity. The effect was attenuated by a long, cyclic side chain. The affinity of tricyclic neuroleptics was only slightly weaker than that of 6-Meo-TH beta C the suggested endogenous ligand. The experiments with other TH beta Cs supported the observation that an electron attracting substituent increases the affinity of a compound to the (3H)imipramine binding sites. Comparison of the binding characteristics of (3H)imipramine to membranes of human brain and thrombocytes as well as those of rat brain and thrombocytes revealed no differences among both species. Furthermore, the displacing potencies of neuroleptics were very similar with only slightly more activity in human tissue. As a methodological aspect the applicability of the "Lowry" method to determine the protein concentration is discussed.