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Positive Allosteric Interaction of Structurally Diverse T-Type Calcium Channel Antagonists
Authors: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 Dai  Owen B. McManus  Kenneth S. Koblan  John J. Renger
Affiliation:1. Department of Depression and Circadian Disorders, Merck Research Laboratories, 770 Sumneytown Pike, WP26-270, West Point, PA, 19486, USA
2. Department of Medicinal Chemistry, Merck Research Laboratories, West Point, PA, 19486, USA
3. Drug Metabolism, Merck Research Laboratories, West Point, PA, 19486, USA
4. Department of Ion Channels, Merck Research Laboratories, Rahway, NJ, 07065, USA
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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