Development of a pharmacophore model for histamine H3 receptor antagonists, using the newly developed molecular modeling program SLATE.
New molecular modeling tools were developed to construct a qualitative pharmacophore model for histamine H3 receptor antagonists. The program SLATE superposes ligands assuming optimum hydrogen bond geometry. One or two ligands are allowed to flex in the procedure, thereby enabling the determination of the bioactive conformation of flexible H3 antagonists. In the derived model, four hydrogen-bonding site points and two hydrophobic pockets available for binding antagonists are revealed. The model results in a better understanding of the structure-activity relationships of H3 antagonists. To validate the model, a series of new antagonists was synthesized. The compounds were designed to interact with all four hydrogen-bonding site points and the two hydrophobic pockets simultaneously. These ligands have high H3 receptor affinity, thereby illustrating how the model can be used in the design of new classes of H3 antagonists.
De Esch
I J
IJ
De Novo Pharmaceuticals, St. Andrews House, 59 St. Andrews Street, CB2 3DD Cambridge, UK. Iwan.deEsch@denovopharma.com
Mills
J E
JE
Perkins
T D
TD
Romeo
G
G
Hoffmann
M
M
Wieland
K
K
Leurs
R
R
Menge
W M
WM
Nederkoorn
P H
PH
Dean
P M
PM
Timmerman
H
H
D000818:Animals; D001593:Benzyl Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D002540:Cerebral Cortex / Q000378:metabolism; D006168:Guinea Pigs; D006633:Histamine Antagonists / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D006636:Histamine Release / Q000187:drug effects; D007093:Imidazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D066298:In Vitro Techniques; D007422:Intestines / Q000187:drug effects / Q000502:physiology; D008024:Ligands; D008958:Models, Molecular; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects / Q000502:physiology; D010880:Piperidines / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D021281:Quantitative Structure-Activity Relationship; D011869:Radioligand Assay; D051381:Rats; D018100:Receptors, Histamine H3 / Q000187:drug effects* / Q000378:metabolism; D012984:Software
D001593:Benzyl Compounds; D006633:Histamine Antagonists; D007093:Imidazoles; D008024:Ligands; D010880:Piperidines; D018100:Receptors, Histamine H3; C052075:thioperamide