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.