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 H(3) receptor antagonist thioperamide were synthesized and evaluated for their histamine H(3) 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 pA(2) value, whereas the same substituents at the para position led to a decrease. However, a fluorine substituent gave a strong decrease in pA(2), regardless of the position. Molecular modeling revealed a QSAR with a correlation (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 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 pA(2) values of these two compounds were in accordance with the measured pA(2) values.
Windhorst
A D
AD
Radionuclide Center, Vrije Universiteit, De Boelelaan 1085c, 1081 HV, Amsterdam, The Netherlands. bwindorst@rnc.vu.nl
Timmerman
H
H
Worthington
E A
EA
Bijloo
G J
GJ
Nederkoorn
P H
PH
Menge
W M
WM
Leurs
R
R
Herscheid
J D
JD
D001593:Benzyl Compounds / Q000138:chemical synthesis / Q000494:pharmacology*; D001665:Binding Sites; D006633:Histamine Antagonists / Q000138:chemical synthesis / Q000494:pharmacology*; D007583:Jejunum / Q000187:drug effects; D008958:Models, Molecular; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects; D010880:Piperidines / Q000138:chemical synthesis / Q000494:pharmacology*; D019275:Radiopharmaceuticals / Q000138:chemical synthesis / Q000494:pharmacology; D018100:Receptors, Histamine H3 / Q000187:drug effects*; D013329:Structure-Activity Relationship
D001593:Benzyl Compounds; D006633:Histamine Antagonists; D010880:Piperidines; D019275:Radiopharmaceuticals; D018100:Receptors, Histamine H3; C052075:thioperamide