The relationship between the lipophilic nature of tricyclic neuroleptics and antidepressants, and histamine release

Abstract

The relative histamine-releasing activity of tricyclic psychoactive drugs, using rat mast cells, was determined. The presence of a halogen or a halogen-containing group at position 2 in the neuroleptics or at position 3 in the antidepressants, and/or carbon instead of nitrogen at position 10 in the neuroleptics or at position 5 in the antidepressants and an unsaturated bond in the aliphatic sidechain increased histamine-releasing activity when compared with unsubstituted homologues. Regarding substitutions of the sidechain the following conclusions for the neuroleptics can be drawn: the presence of a piperidine or piperazine ring in the sidechain increased histamine-releasing activity. From these substituted compounds, those having a methyl group at the terminal nitrogen were more active than homologues with an alcohol group at the nitrogen. For antidepressants, aliphatic tertiary amines were more active than secondary amines. Lipophilic nature was expressed as the partition coefficients of the drugs in a octanol-buffer and chloroform-buffer system. A significant correlation was found, between lipophilic nature and histamine-releasing activity.