Using electrophysiology and in silico three-dimensional modeling to reduce human Ether-à-go-go related gene K(+) channel inhibition in a histamine H3 receptor antagonist program.

Abstract

The histamine H3 receptor (H3R) plays a regulatory role in the presynaptic release of histamine and several other neurotransmitters, and thus, it is an attractive target for central nervous system indications including cognitive disorders, narcolepsy, attention-deficit hyperactivity disorder, and pain. The development of H3R antagonists was complicated by the similarities between the pharmacophores of H3R and human Ether-à-go-go related gene (hERG) channel blockers, a fact that probably prevented promising compounds from being progressed into the clinic. Using a three-dimensional in silico modeling approach complemented with automated and manual patch clamping, we were able to separate these two pharmacophores and to develop highly potent H3R antagonists with reduced risk of hERG liabilities from initial hit series with low selectivity identified in a high-throughput screening campaign.

• Authors: Adam J Davenport, Clemens Möller, Alexander Heifetz, Michael P Mazanetz, Richard J Law, Andreas Ebneth, Mark J Gemkow
• Journal: Assay and drug development technologies (Assay Drug Dev Technol) Vol. 8 Issue 6 Pg. 781-9 (Dec 2010) ISSN: 1557-8127 [Electronic] United States
• PMID: 21133680 (Publication Type: Journal Article)

Chemical References

• Ether-A-Go-Go Potassium Channels
• Histamine H3 Antagonists
• Receptors, Histamine H3

Topics

• Animals
• Computer Simulation
• Cricetinae
• Cricetulus
• Drug Design
• Drug Discovery
• Ether-A-Go-Go Potassium Channels (antagonists & inhibitors, metabolism)
• High-Throughput Screening Assays
• Histamine H3 Antagonists (adverse effects, chemistry, metabolism, pharmacology)
• Humans
• Models, Molecular
• Patch-Clamp Techniques
• Receptors, Histamine H3 (metabolism)
• Structure-Activity Relationship