2. Academic Validation
  3. Positive allosteric interaction of structurally diverse T-type calcium channel antagonists

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

  • Cell Biochem Biophys. 2009;55(2):81-93. doi: 10.1007/s12013-009-9057-4.
Victor N Uebele 1,  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 Dai,  Owen B McManus,  Kenneth S Koblan,  John J Renger
Affiliations

Affiliation

  • 1 Department of Depression and Circadian Disorders, Merck Research Laboratories, West Point, PA 19486, USA. victor_uebele@merck.com
PMID: 19582593 DOI: 10.1007/s12013-009-9057-4
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.

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