HETEROARYLAMINOETHYL AND HETEROARYLTHIOETHYL IMIDAZOLES - SYNTHESIS AND H-3 RECEPTOR AFFINITY

The synthesis of new H-3-receptor antagonists, 4-(2-heteroarylaminoethyl) and 4-(2-heteroarylthioethyl) imidazoles and their H-3-receptor affinity obtained from competitive binding curves vs [H-3]-N-alpha-methylhistamine ([H-3]NAMHA) on rat brain cortex membranes are described. These compounds are derived from structural modulations of thioperamide and were synthesized in order to study binding interactions with H-3-receptors and find alternative lead compounds with H-3-receptor antagonist activity. The new compounds differ from thioperamide by the following features: 1) the N-cyclohexylcarbothioamide moiety of thioperamide has been replaced by a benzothiazole (1); 2) the piperidine ring has been replaced by more flexible aminoethyl and thioethyl chains, in order to lower the excessive rigidity of 1 and to test the importance of the tertiary piperidine nitrogen; and 3) the benzothiazole moiety of 1 has been replaced by other heterocyclic nuclei, endowed with different lipophilic, steric and hydrogen-bonding features. Some of the compounds tested showed good affinity for central H-3-receptors (pK(i) range: 5.89-7.96) and can be considered as lead compounds for further optimization studies. The most lipophilic compounds showed higher affinities among benzo-condensed compounds, while imidazolylthioethyl imidazoles were more potent in displacing [H-3]NAMHA than thiazolylthioethyl and thiazolylaminoethyl imidazoles which suggests an interaction between the annular NH of the imidazolylthioethyl moiety and the binding site.