Development of a pharmacophore model for histamine H3 receptor antagonists, using the newly developed molecular modeling program SLATE

I J De Esch; J E Mills; T D Perkins; G Romeo; M Hoffmann; K Wieland; R Leurs; W M Menge; P H Nederkoorn; P M Dean; H Timmerman

doi:10.1021/jm001109k

Development of a pharmacophore model for histamine H3 receptor antagonists, using the newly developed molecular modeling program SLATE

J Med Chem. 2001 May 24;44(11):1666-74. doi: 10.1021/jm001109k.

Authors

I J De Esch¹, J E Mills, T D Perkins, G Romeo, M Hoffmann, K Wieland, R Leurs, W M Menge, P H Nederkoorn, P M Dean, H Timmerman

Affiliation

¹ De Novo Pharmaceuticals, St. Andrews House, 59 St. Andrews Street, CB2 3DD Cambridge, UK. Iwan.deEsch@denovopharma.com

PMID: 11356102
DOI: 10.1021/jm001109k

Abstract

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Benzyl Compounds / chemical synthesis
Benzyl Compounds / chemistry
Benzyl Compounds / metabolism
Benzyl Compounds / pharmacology
Cerebral Cortex / metabolism
Guinea Pigs
Histamine Antagonists / chemical synthesis
Histamine Antagonists / chemistry*
Histamine Antagonists / metabolism
Histamine Antagonists / pharmacology
Histamine Release / drug effects
Imidazoles / chemical synthesis
Imidazoles / chemistry
Imidazoles / metabolism
Imidazoles / pharmacology
In Vitro Techniques
Intestines / drug effects
Intestines / physiology
Ligands
Models, Molecular
Muscle Contraction / drug effects
Muscle, Smooth / drug effects
Muscle, Smooth / physiology
Piperidines / chemical synthesis
Piperidines / chemistry
Piperidines / metabolism
Piperidines / pharmacology
Quantitative Structure-Activity Relationship
Radioligand Assay
Rats
Receptors, Histamine H3 / drug effects*
Receptors, Histamine H3 / metabolism
Software

Substances

Benzyl Compounds
Histamine Antagonists
Imidazoles
Ligands
Piperidines
Receptors, Histamine H3
thioperamide