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

The synthesis of new H-3-receptor antagonists, 4-(2-heteroarylaminoeth yl) and 4-(2-heteroarylthioethyl) imidazoles and their H-3-receptor af finity obtained from competitive binding curves vs [H-3]-N-alpha-methy lhistamine ([H-3]NAMHA) on rat brain cortex membranes are described. T hese 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 antago nist activity. The new compounds differ from thioperamide by the follo wing features: 1) the N-cyclohexylcarbothioamide moiety of thioperamid e has been replaced by a benzothiazole (1); 2) the piperidine ring has been replaced by more flexible aminoethyl and thioethyl chains, in or der to lower the excessive rigidity of 1 and to test the importance of the tertiary piperidine nitrogen; and 3) the benzothiazole moiety of 1 has been replaced by other heterocyclic nuclei, endowed with differe nt lipophilic, steric and hydrogen-bonding features. Some of the compo unds tested showed good affinity for central H-3-receptors (pK(i) rang e: 5.89-7.96) and can be considered as lead compounds for further opti mization studies. The most lipophilic compounds showed higher affiniti es among benzo-condensed compounds, while imidazolylthioethyl imidazol es were more potent in displacing [H-3]NAMHA than thiazolylthioethyl a nd thiazolylaminoethyl imidazoles which suggests an interaction betwee n the annular NH of the imidazolylthioethyl moiety and the binding sit e.