Positive allosteric interaction of structurally diverse T-type calcium channel antagonists

Victor N. Uebele, Cindy E. Nuss, Steven V. Fox, Susan L. Garson, Razvan Cristescu, Scott M. Doran, Richard L. Kraus, Vincent P. Santarelli, Yuxing Li, James C. Barrow, Zhi Qiang Yang, Kelly Ann S. Schlegel, Kenneth E. Rittle, Thomas S. Reger, Rodney A. Bednar, Wei Lemaire, Faith A. Mullen, Jeanine E. Ballard, Cuyue Tang, Ge DaiOwen B. McManus, Kenneth S. Koblan, John J. Renger

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
Pages (from-to)81-93
Number of pages13
JournalCell Biochemistry and Biophysics
Volume55
Issue number2
DOIs
StatePublished - Sep 1 2009
Externally publishedYes

Keywords

  • Absence epilepsy
  • CACNA1I
  • CaV3
  • Radioligand
  • Seizure
  • Synergy
  • T-type calcium channel

ASJC Scopus subject areas

  • Biophysics
  • Biochemistry
  • Cell Biology

Fingerprint Dive into the research topics of 'Positive allosteric interaction of structurally diverse T-type calcium channel antagonists'. Together they form a unique fingerprint.

  • Cite this

    Uebele, V. N., Nuss, C. E., Fox, S. V., Garson, S. L., Cristescu, R., Doran, S. M., Kraus, R. L., Santarelli, V. P., Li, Y., Barrow, J. C., Yang, Z. Q., Schlegel, K. A. S., Rittle, K. E., Reger, T. S., Bednar, R. A., Lemaire, W., Mullen, F. A., Ballard, J. E., Tang, C., ... Renger, J. J. (2009). Positive allosteric interaction of structurally diverse T-type calcium channel antagonists. Cell Biochemistry and Biophysics, 55(2), 81-93. https://doi.org/10.1007/s12013-009-9057-4