Positive allosteric interaction of structurally diverse T-type calcium channel antagonists.
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Uebele VN, Nuss CE, Fox SV, Garson SL, Cristescu R, Doran SM, Kraus RL, Santarelli VP, Li Y, Barrow JC, Yang ZQ, Schlegel KA, Rittle KE, Reger TS, Bednar RA, Lemaire W, Mullen FA, Ballard JE, Tang C, Dai G, McManus OB, Koblan KS, Renger JJ
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. Epub 2009 Jul 7.
- PubMed ID
- 19582593 [ View in PubMed]
- 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.
DrugBank Data that Cites this Article
- Drug Targets
Drug Target Kind Organism Pharmacological Action Actions Flunarizine Voltage-dependent T-type calcium channel subunit alpha-1G Protein Humans YesInhibitorDetails Flunarizine Voltage-dependent T-type calcium channel subunit alpha-1H Protein Humans YesInhibitorDetails Flunarizine Voltage-dependent T-type calcium channel subunit alpha-1I Protein Humans YesInhibitorDetails