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.
authors: Department of Depression and Circadian Disorders, Merck Research Laboratories, West Point, PA 19486, USA. victor_uebele@merck.com
authors: Victor N
authors: VN
authors: Uebele
authors: Cindy E
authors: CE
authors: Nuss
authors: Steven V
authors: SV
authors: Fox
authors: Susan L
authors: SL
authors: Garson
authors: Razvan
authors: R
authors: Cristescu
authors: Scott M
authors: SM
authors: Doran
authors: Richard L
authors: RL
authors: Kraus
authors: Vincent P
authors: VP
authors: Santarelli
authors: Yuxing
authors: Y
authors: Li
authors: James C
authors: JC
authors: Barrow
authors: Zhi-Qiang
authors: ZQ
authors: Yang
authors: Kelly-Ann S
authors: KA
authors: Schlegel
authors: Kenneth E
authors: KE
authors: Rittle
authors: Thomas S
authors: TS
authors: Reger
authors: Rodney A
authors: RA
authors: Bednar
authors: Wei
authors: W
authors: Lemaire
authors: Faith A
authors: FA
authors: Mullen
authors: Jeanine E
authors: JE
authors: Ballard
authors: Cuyue
authors: C
authors: Tang
authors: Ge
authors: G
authors: Dai
authors: Owen B
authors: OB
authors: McManus
authors: Kenneth S
authors: KS
authors: Koblan
authors: John J
authors: JJ
authors: Renger
mesh_terms: D000494:Allosteric Regulation / Q000187:drug effects; D000495:Allosteric Site / Q000187:drug effects; D000818:Animals; D002121:Calcium Channel Blockers / Q000737:chemistry / Q000494:pharmacology*; D020747:Calcium Channels, T-Type / Q000378:metabolism*; D002478:Cells, Cultured; D006801:Humans; D008297:Male; D015394:Molecular Structure; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D002121:Calcium Channel Blockers; D020747:Calcium Channels, T-Type