QSAR STUDY ON H3-RECEPTOR AFFINITY OF BENZOTHIAZOLE DERIVATIVES OF THIOPERAMIDE

Starting from the structure of thioperamide, a known H-3-antagonist, a new series of compounds with a benzothiazole nucleus instead of the c yclohexylcarbothioamide moiety was synthesized. Various substituents, selected by experimental design, were introduced in position 6 of the benzothiazole nucleus, in order to change its physico-chemical charact eristics. The lipophilicity of the synthesized compounds was measured by means of RP-HPLC, and their H-3-receptor affinity was evaluated by competitive binding assays on rat cortex synaptosomes, with the labell ed ligand N(alpha)-[H-3]methylhistamine. A QSAR analysis was performed on the experimental data, using also substituent constants taken from the literature. The newly synthesized compounds showed lower H-3-affi nities than thioperamide; quantitative structure-activity relationship s, described by models obtained with PLS and MRA techniques, were obse rved among benzothiazole derivatives. According to these relationships , any attempt to improve the potency of these compounds should involve the substitution of the benzothiazole moiety with less bulky and/or m ore flexible structures, which should also be less lipophilic and allo w better electronic interactions with the binding site. enzothiazol-2- yl)-4-[(1H)-imidazol-4-yl]piperidine represents a limit structure for H-3-activity, since it seems impossible to improve its affinity by mea ns of substitution in the studied position of the benzothiazole nucleu s, as shown by predictions performed by a PLS model.