Characterization of the binding site of the Histamine H3 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 H3 receptor antagonist thioperamide were synthesized and evaluated for their histamine H3 receptor activity on the guinea pig jejunum. Incorporation of Cl, Br, and I at the ortho position of the benzyl moiety led to an increase of the pA2 value, whereas the same substituents at the para position led to a decrease. However, a fluorine substituent gave a strong decrease in pA2, regardless of the position. Molecular modeling revealed a QSAR with a correlation (r = 0.93) between the pA2 and the dihedral angle between the thiourea and the benzyl moiety and the calculated electron density on the substituted carbon atom. To verify whether this QSAR model had a predictive value, the ortho tert-butyl and methyl analogues were synthesized and evaluated. Indeed it was shown that the predicted pA2 values of these two compounds were in accordance with the measured pA2 values.