1. 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
- Author
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Alexander Heifetz, Mark J. Gemkow, Michael P. Mazanetz, Richard J. Law, Clemens Möller, Andreas Ebneth, and Adam James Davenport
- Subjects
Models, Molecular ,Patch-Clamp Techniques ,In silico ,hERG ,Biology ,Pharmacology ,Structure-Activity Relationship ,chemistry.chemical_compound ,Cricetulus ,Cricetinae ,Drug Discovery ,medicine ,Animals ,Humans ,Receptors, Histamine H3 ,Computer Simulation ,Channel blocker ,Antagonist ,medicine.disease ,Ether-A-Go-Go Potassium Channels ,High-Throughput Screening Assays ,chemistry ,Drug Design ,biology.protein ,Molecular Medicine ,Histamine H3 receptor ,Pharmacophore ,Histamine ,Histamine H3 Antagonists ,Narcolepsy - 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-a-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.
- Published
- 2010
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