Positive Allosteric Interaction of Structurally Diverse T-Type Calcium Channel Antagonists
| Autor: | Scott M. Doran, Kenneth E. Rittle, Yuxing Li, Cindy E. Nuss, Faith A. Mullen, Jeanine E. Ballard, Razvan Cristescu, Thomas S. Reger, Zhi-Qiang Yang, John J. Renger, Kenneth S. Koblan, Owen B. McManus, Vincent P. Santarelli, Rodney A. Bednar, Victor N. Uebele, Cuyue Tang, Susan L. Garson, Kelly-Ann S. Schlegel, Richard L. Kraus, Æ James C. Barrow, Ge Dai, Wei Lemaire, Steven V. Fox |
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| Rok vydání: | 2009 |
| Předmět: |
Male
Allosteric regulation Biophysics Pharmacology Biochemistry Rats Sprague-Dawley Calcium Channels T-Type Structure-Activity Relationship Allosteric Regulation Genetic model Radioligand medicine Animals Humans Rats Wistar Cells Cultured Mibefradil Molecular Structure Voltage-dependent calcium channel Chemistry Calcium channel T-type calcium channel Antagonist Stereoisomerism Cell Biology General Medicine Calcium Channel Blockers Rats Allosteric Site medicine.drug |
| Zdroj: | Cell Biochemistry and Biophysics. 55:81-93 |
| ISSN: | 1559-0283 1085-9195 |
| Popis: | Low-voltage-activated (T-type) calcium channels play a role in diverse physiological responses including neuronal burst firing, hormone secretion, and cell growth. To better understand the biological role and therapeutic potential of the target, a number of structurally diverse antagonists have been identified. Multiple drug interaction sites have been identified for L-type calcium channels, suggesting a similar possibility exists for the structurally related T-type channels. Here, we radiolabel a novel amide T-type calcium channel antagonist (TTA-A1) and show that several known antagonists, including mibefradil, flunarizine, and pimozide, displace binding in a concentration-dependent manner. Further, we identify a novel quinazolinone T-type antagonist (TTA-Q4) that enhanced amide radioligand binding, increased affinity in a saturable manner and slowed dissociation. Functional evaluation showed these compounds to be state-dependent antagonists which show a positive allosteric interaction. Consistent with slowing dissociation, the duration of efficacy was prolonged when compounds were co-administered to WAG/Rij rats, a genetic model of absence epilepsy. The development of a T-type calcium channel radioligand has been used to demonstrate structurally distinct TTAs interact at allosteric sites and to confirm the potential for synergistic inhibition of T-type calcium channels with structurally diverse antagonists. |
| Databáze: | OpenAIRE |
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