Characterization of the binding site of the histamine H-3 receptor. 2. Synthesis, in vitro pharmacology, and QSAR of a series of monosubstituted benzyl analogues of thioperamide

A series of monosubstituted benzyl analogues of the histamine Hg receptor a ntagonist thioperamide were synthesized and evaluated for their histamine H -3 receptor activity on the guinea pig jejunum. Incorporation of Cl, Br, an d I at the ortho position of the benzyl moiety led to an increase of the pA (2) value, whereas the same substituents at the para position led to a decr ease. However, a fluorine substituent gave a strong decrease in pA(2), rega rdless of the position. Molecular modeling revealed a QSAR with a correlati on (r = 0.93) between the pA(2) and the dihedral angle between the thiourea and the benzyl moiety and the calculated electron density on the substitut ed carbon atom. To verify whether this QSAR model had a predictive value, t he ortho tert-butyl and methyl analogues were synthesized and evaluated. In deed it was shown that the predicted pA(2) values of these two compounds we re in accordance with the measured pA(2) values.