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 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 & 3 others Owen 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 2009
Externally publishedYes

Fingerprint

T-Type Calcium Channels
Calcium Channel Blockers
Amides
Mibefradil
Quinazolinones
Drug interactions
Flunarizine
Allosteric Site
Pimozide
Absence Epilepsy
L-Type Calcium Channels
Genetic Models
Cell growth
Drug Interactions
Rats
Hormones
Electric potential
Growth

Keywords

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

ASJC Scopus subject areas

  • Biophysics
  • Biochemistry
  • Cell Biology

Cite this

Uebele, V. N., Nuss, C. E., Fox, S. V., Garson, S. L., Cristescu, R., Doran, S. M., ... 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

Positive allosteric interaction of structurally diverse T-type calcium channel antagonists. / Uebele, Victor N.; Nuss, Cindy E.; Fox, Steven V.; Garson, Susan L.; Cristescu, Razvan; Doran, Scott M.; Kraus, Richard L.; Santarelli, Vincent P.; Li, Yuxing; Barrow, James; Yang, Zhi Qiang; Schlegel, Kelly Ann S; Rittle, Kenneth E.; Reger, Thomas S.; Bednar, Rodney A.; Lemaire, Wei; Mullen, Faith A.; Ballard, Jeanine E.; Tang, Cuyue; Dai, Ge; McManus, Owen B.; Koblan, Kenneth S.; Renger, John J.

In: Cell Biochemistry and Biophysics, Vol. 55, No. 2, 09.2009, p. 81-93.

Research output: Contribution to journalArticle

Uebele, VN, Nuss, CE, Fox, SV, Garson, SL, Cristescu, R, Doran, SM, Kraus, RL, Santarelli, VP, Li, Y, Barrow, J, Yang, ZQ, Schlegel, KAS, Rittle, KE, Reger, TS, Bednar, RA, Lemaire, W, Mullen, FA, Ballard, JE, Tang, C, Dai, G, McManus, OB, Koblan, KS & Renger, JJ 2009, 'Positive allosteric interaction of structurally diverse T-type calcium channel antagonists', Cell Biochemistry and Biophysics, vol. 55, no. 2, pp. 81-93. https://doi.org/10.1007/s12013-009-9057-4
Uebele, Victor N. ; Nuss, Cindy E. ; Fox, Steven V. ; Garson, Susan L. ; Cristescu, Razvan ; Doran, Scott M. ; Kraus, Richard L. ; Santarelli, Vincent P. ; Li, Yuxing ; Barrow, James ; Yang, Zhi Qiang ; Schlegel, Kelly Ann S ; Rittle, Kenneth E. ; Reger, Thomas S. ; Bednar, Rodney A. ; Lemaire, Wei ; Mullen, Faith A. ; Ballard, Jeanine E. ; Tang, Cuyue ; Dai, Ge ; McManus, Owen B. ; Koblan, Kenneth S. ; Renger, John J. / Positive allosteric interaction of structurally diverse T-type calcium channel antagonists. In: Cell Biochemistry and Biophysics. 2009 ; Vol. 55, No. 2. pp. 81-93.
@article{8cd8ce8d121f45f393d8a9f39e7c6bde,
title = "Positive allosteric interaction of structurally diverse T-type calcium channel antagonists",
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.",
keywords = "Absence epilepsy, CACNA1I, CaV3, Radioligand, Seizure, Synergy, T-type calcium channel",
author = "Uebele, {Victor N.} and Nuss, {Cindy E.} and Fox, {Steven V.} and Garson, {Susan L.} and Razvan Cristescu and Doran, {Scott M.} and Kraus, {Richard L.} and Santarelli, {Vincent P.} and Yuxing Li and James Barrow and Yang, {Zhi Qiang} and Schlegel, {Kelly Ann S} and Rittle, {Kenneth E.} and Reger, {Thomas S.} and Bednar, {Rodney A.} and Wei Lemaire and Mullen, {Faith A.} and Ballard, {Jeanine E.} and Cuyue Tang and Ge Dai and McManus, {Owen B.} and Koblan, {Kenneth S.} and Renger, {John J.}",
year = "2009",
month = "9",
doi = "10.1007/s12013-009-9057-4",
language = "English (US)",
volume = "55",
pages = "81--93",
journal = "Cell Biochemistry and Biophysics",
issn = "1085-9195",
publisher = "Humana Press",
number = "2",

}

TY - JOUR

T1 - Positive allosteric interaction of structurally diverse T-type calcium channel antagonists

AU - Uebele, Victor N.

AU - Nuss, Cindy E.

AU - Fox, Steven V.

AU - Garson, Susan L.

AU - Cristescu, Razvan

AU - Doran, Scott M.

AU - Kraus, Richard L.

AU - Santarelli, Vincent P.

AU - Li, Yuxing

AU - Barrow, James

AU - Yang, Zhi Qiang

AU - Schlegel, Kelly Ann S

AU - Rittle, Kenneth E.

AU - Reger, Thomas S.

AU - Bednar, Rodney A.

AU - Lemaire, Wei

AU - Mullen, Faith A.

AU - Ballard, Jeanine E.

AU - Tang, Cuyue

AU - Dai, Ge

AU - McManus, Owen B.

AU - Koblan, Kenneth S.

AU - Renger, John J.

PY - 2009/9

Y1 - 2009/9

N2 - 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.

AB - 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.

KW - Absence epilepsy

KW - CACNA1I

KW - CaV3

KW - Radioligand

KW - Seizure

KW - Synergy

KW - T-type calcium channel

UR - http://www.scopus.com/inward/record.url?scp=71449104987&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=71449104987&partnerID=8YFLogxK

U2 - 10.1007/s12013-009-9057-4

DO - 10.1007/s12013-009-9057-4

M3 - Article

VL - 55

SP - 81

EP - 93

JO - Cell Biochemistry and Biophysics

JF - Cell Biochemistry and Biophysics

SN - 1085-9195

IS - 2

ER -