Physicochemical Determinants for Drug Induced Blockade of HERG Potassium Channels: Effect of Charge and Charge Shielding
| Autor: | Eric S. Hayes, Gregory B Beatch, Alexander Zolotoy, Michael J A Walker, Bertrand Plouvier, Richard A. Wall |
|---|---|
| Rok vydání: | 2003 |
| Předmět: |
Potassium Channels
Ketone Chemical Phenomena Stereochemistry hERG Inhibitory Concentration 50 Deprotonation Torsades de Pointes Potassium Channel Blockers Animals Humans Molecule Amines Cation Transport Proteins Pharmacology chemistry.chemical_classification Molecular Structure Voltage-gated ion channel biology Chemistry Physical Arrhythmias Cardiac Heart Hematology Ether-A-Go-Go Potassium Channels Potassium channel Electrophysiology chemistry Potassium Channels Voltage-Gated Alkoxy group biology.protein Cardiology and Cardiovascular Medicine Anti-Arrhythmia Agents |
| Zdroj: | Current Medicinal Chemistry-Cardiovascular & Hematological Agents. 1:225-241 |
| ISSN: | 1568-0169 |
| Popis: | The data on the activities of all previously described HERG blockers and of the most widely cited I(Kr) blockers were analyzed with respect to the effect of potential charged center(s) and its shielding by surrounding structural elements. The following model was considered: the less shielding of the charged form of the drug occurs, the easier its deprotonation will be and the less potency of the blockade of HERG/I(Kr) channels will be. Tertiary amines which form ammonium ions shielded by two structural fragments of the drug molecule were found to be potent HERG/I(Kr) blockers with IC501 microM (16 of 19 compounds, 84%). However, if the charged center was found at the molecular periphery as such groups as dimethylamino, N-methylpiperidino, N-methylpiperazino, N-methylpyrrolidino, pyrrolidino, imidazolo and partial periphery (diethylamino), then only moderate potency for HERG blockade with 1 microMIC5010 microM (8 of 11 compounds; 73%) was observed. Similarly, 27 of 32 weak HERG blockers ( IC5010 microM) were found to be primary or secondary amines, or neutral or very weakly basic compounds. Ions of primary and secondary amines are susceptible to the fast deprotonation of the charged center and they, as well as non-charged compounds, have a low probability of induction of Torsades de Pointes (TdP). Conformational analysis and modeling of the interaction of the charged fragment of the drugs with acetone, a system that mimics a ketone fragment of HERG/I(Kr) channel, supports preference of the conformation with the shielded charged center for potent HERG/I(Kr) blockers. The absence of stereospecificity of HERG/I(Kr) blockade observed in most of the published studies reinforces the importance of charged center shielding as a key parameter. We suggest that the introduction of a hydroxy group at position 3 relative to a tertiary ammonium charged center, or the introduction of hydroxy, alkoxy or amino groups at position 2 relative to the nitrogen center of an aromatic system, should provide easy access of a water molecule to the proton, thereby facilitating deprotonation and thus leading to a moderate or weak HERG/I(Kr) blockade and a reduced risk of TdP. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|