Calcium channel T-type

Succinimides. Ethosuximide [77-67-8] C2H22NO2 (41) and the related succinknide, methsuximide [77-41-8] C22H23NO2 (42) are used in absence seizure treatment. Like the other anticonvulsants discussed, the mechanism of action of the succinirnides is unclear. Effects on T-type calcium channels and -ATPase activity have been reported (20). Ethosuximide has significant CNS and gastrointestinal (GI) side effect HabiUties (13). 

Voltage-dependent Ca2+ channels are a family of multi-subunit complexes of five proteins responding to membrane depolarisation with channel opening allowing the influx of calcium into a cell. Voltage-dependent calcium channels are subdivided into three subfamilies the HVA DHP-sensitive L-type calcium channels, the HVA DHP-insensitive calcium channels and the LVA T-type calcium channels [2]. 

Perez-Reyes E (2003) Molecular physiology of low-voltage-activated t-type calcium channels. Physiol Rev 83 117-161... 

T-type calcium channel Maybridge (55 K) and ion channel inhibitor db (8 K), Catalyst search 3 hits of 25 tested [123]... 

Calcium channels have been shown to play a role in epilepsy as well [23]. Currently used antiepileptic drugs exhibit a wide spectrum of activity, including modulation of voltage-gated sodium and calcium channels. T-type calcium channels have been demonstrated to play an important role in absence epilepsy, a specific form of epilepsy characterized by brief lapses in consciousness correlated with spike-and-wave discharges in the electroencephalogram [14,24-28]. Ethosuximide 1 has been shown to block T-type calcium channels and is used clinically to treat absence epilepsy [25]. Several selective small-molecule T-type calcium channel antagonists have demonstrated efficacy in rodent epilepsy models (vide infra). 

Several diverse structural classes of T-type calcium channel antagonists have been reported over the last decade [46,47]. This section focuses on recent literature reports of CNS T-type antagonists since 2008. 

The two most frequently studied compounds with T-type calcium channel antagonist properties are ethosuximide 1 and mibefradil 3. However, the modest potency of ethosuximide ( 200 pM) [48] and the poor selectivity of mibefradil [49] make these compounds suboptimal tools for the investigation of these channels. Guided by a pharmacophore model [50], several analogs of 3 were prepared. Compound 4 represents the most potent compound identified (IC50 8 nM, patch-clamp assay) with good selectivity over the L-type calcium channel [51], Compound 4 showed a modest brain-to-plasma ratio (0.25) after oral dosing to rats at 50 mg/kg. However, no in vivo efficacy assay results have been reported with this compound. 

A series of 2-amino-3/4-dihydro quinazolines have been extensively explored as selective T-type calcium channel antagonists. A recent disclosure included KYS05090 (9) with an IC50 of 41 nM on the Cav3.1 subtype of the T-type channel and 120-fold selectivity versus the N-type calcium channel Cav2.2 [55]. A pharmacophore model was recently published based on this and related structures [56], but no other selectivity or in vivo activity have been disclosed since the original report. 

Dogrul, A., Yesilyurt, O., Isimer, A., Guzeldemir, M.E. L-type and T-type calcium channel blockade potentiate the analgesic effects of morphine and selective mu opioid agonist, but not to selective delta and kappa agonist at the level of the spinal cord in mice, Pain 2001, 93, 61-68. 

T-type calcium channels play critical roles in shaping the electrical and plastic properties of neurons and are also implicated in hormone secretion, differentiation and muscle development (Huguenard, 1996 Perez-Reyes, 2003). In thalamic reticular and relay neurons, T-type channels contribute to rhythmic rebound burst firing and spindle waves associated with slow-wave sleep. T-type channels also play crucial roles in dendritic integration and calcium-mediated spiking in hippocampal pyramidal cells, and in synaptic release at olfactory dendrodendritic... 

Chemin J, Monteil A, Perez-Reyes E, Bourinet E, Nargeot J, Lory P (2002) Specific contribution of human T-type calcium channel isotypes (alpha(lG), alpha(lH) and alpha(ll)) to neuronal excitability. J Physiol 540 3-14. 

Khosravani H, Altier C, Simms B, Hamming KS, Snutch TP, Mezeyova J, McRory JE, Zamponi GW (2004) Gating effects of mutations in the Cav3.2 T-type calcium channel associated with childhood absence epilepsy. J Biol Chem 279 9681-9684. 

McKay BE, McRory JE, Molineux ML, Hamid J, Snutch TP, Zamponi GW, Turner RW (2006) Ca(V)3 T-type calcium channel isoforms differentially distribute to somatic and dendritic compartments in rat central neurons. Eur J Neurosci 24 2581-2594. 

McRory JE, Santi CM, Hamming KS, Mezeyova J, Sutton KG, Baillie DL, Stea A, Snutch TP (2001) Molecular and functional characterization of a family of rat brain T-type calcium channels. J Biol Chem 276 3999 1011. 

Peloquin JB, Khosravani H, Barr W, Bladen C, Evans R, Mezeyova J, Parker D, Snutch TP, McRory JE, Zamponi GW (2006) Functional analysis of Ca3.2 T-type calcium channel mutations linked to childhood absence epilepsy. Epilepsia 47 655-658. 

Snutch TP, David LS (2006) T-Type Calcium Channels An Emerging Therapeutic Target for the Treatment of Pain. Drug Development Research 404-415. 

Talley EM, Cribbs LL, Lee JH, Daud A, Perez-Reyes E, Bayliss DA (1999) Differential distribution of three members of a gene family encoding low voltage-activated (T-type) calcium channels. J Neurosci 19 1895-1911. 

Vitko I, Chen Y, Arias JM, Shen Y, Wu XR, Perez-Reyes E (2005) Functional characterization and neuronal modeling of the effects of childhood absence epilepsy variants of CACNA1H, a T-type calcium channel. J Neurosci 25 4844-4855. 

Gray, L. S. and Macdonald, T. L., 2006, The pharmacology and regulation of T type calcium channels new opportunities for unique therapeutics for cancer. Cell Calcium 40, 115-20. 

Mariot, P., Vanoverberghe, K., Lalevee, N., Rossier, M. F. and Prevarskaya, N., 2002, Overexpression of an alpha 1H (Cav3.2) T-type calcium channel during neuroendocrine differentiation of human... 

Nikonenko I., Bancila M., Bloc A., Muller D., and Bijlenga P. 2005 Inhibition of T-type calcium channels protects neurons from delayed ischemia-induced damage. Mol Pharmacol 68, 84-89. 

Lee A, Wong ST, Gallagher D, Li B, Storm DR, Scheuer T, Catterall WA (1999a) Ca2+/calmodulin binds to and modulates P/Q-type calcium channels. Nature 399 155-9 Lee JH, Daud AN, Cribbs LL, Lacerda AE, Pereverzev A, Klockner U, Schneider T, Perez-Reyes E (1999b) Cloning and expression of a novel member of the low voltage-activated T-type calcium channel family. J Neurosci 19 1912-21... 

McDonough SI, Boland LM, Mintz IM, Bean BP (2002) Interactions among toxins that inhibit N-type and P-type calcium channels. J Gen Physiol 119 313-28 McDonough SI, Mintz IM, Bean BP (1997) Alteration of P-type calcium channel gating by the spider toxin omega-Aga-IVA. Biophys J 72 2117-28 McRory JE, Santi CM, Hamming KS, Mezeyova J, Sutton KG, Baillie. DL, Stea A, Snutch TP (2001) Molecular and functional characterization of a family of rat brain T-type calcium channels. J Biol Chem 276 3999 011... 

Monteil A, Chemin J, Bourinet E, Mennessier G, Lory P, Nargeot J (2000) Molecular and functional properties of the human alpha(lG) subunit that forms T-type calcium channels. J Biol Chem 275 6090-100... 

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