Calcium channel activators/modulators

Table 7 Modulation of hERG and L-type calcium channel activity following fluorine substitution...

Other actions of some anticonvulsants include inhibition of the enzyme carbonic anhydrase, negative modulation of calcium channel activity, and actions on second messenger systems, including inhibition of phosphokinase C. Beyond the second messenger, there is the possibility that second messenger systems may be affected, analogously to what is hypothesized for lithium. 

Barrett CF, Rittenhouse AR (2000) Modulation of N-type calcium channel activity by G-proteins and protein kinase C. J Gen Physiol 115 277-86... 

Agus Z S, Kelepouris E, Dukes I et al 1989 Cytosolic magnesium modulates calcium channel activity in mammalian ventricular cells. American Journal of Physiology 256 C452-C455 Ajayi A A, Campbell B C, Meredith P A et al 1985 The effect of captopril on the reflex control heart rate possible mechanisms. British Journal of Clinical Pharmacology 20 17-25... 

In conclusion, normally, low concentrations of palytoxin are sufficient to produce a massive increase in the permeability of cells to cations. Palytoxin stimulates sodium influx and potassimn efflux, and thus produces depolarization of the membrane in several cellular systems. In excitable systems, palytoxin-stimiflated depolarization can modulate calcium channel activity, resulting in a rise in the intracellular calcimn concentration, which can afterwards regulate calcium-dependent pathways and their related events. In muscle, depolarization causes calcium release and contraction. In vivo, the depolarization caused by the toxin can produce vasoconstriction, which can be lethal. In other systems, palytoxin-regulated events may not require an increase in the intracellular calcimn concentration. Whether the high cytotoxicity of palytoxin is merely a consequence of its disruption of the ionic enviromnent of the cell remains to be elucidated. 

Functionally, the Dl-like receptors (Dl, D5) are coupled to the G protein Gas and thus can stimulate adenylyl cyclase. The D2-like receptors (D2, D3, and D4) couple to pertussis toxin sensitive G proteins (Gai/0), and consequently inhibit adenylyl cyclase activity. While the Dl-like receptors almost exclusively signal through Gas-mediated activation of adenylyl cyclase, the D2-like receptors have been reported to modulate the activity of a plethora of signaling molecules and pathways. Many of these actions are mediated through the G(3y subunit. Some of these molecules and pathways include the calcium channels, potassium channels, sodium-hydrogen exchanger, arachidonic acid release, and mitogen-activated protein kinase pathways. 

Gabapentin Modulate calcium channels and enhance GABA activity Loading dose Not recommended due to short half-life Maintenance dose 900-3600 mg/day in 3-4 divided doses (doses up to 1 0,000 mg/day have been tolerated) Half-life Not established 5-7 hours (proportional to creatinine clearance) Apparent volume of distribution 0.6-0.8 L/kg Protein binding less than 10% Primary elimination route Renal Drowsiness, sedation Peripheral edema, weight gain... 

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). 

Assays of acetyl- and butyrylcholine esterases inhibition, as well as of modulation of calcium channels and nicotinic receptors have been conducted in vivo. Moreover, their interaction with the active center of acetylcholine esterase has been simulated by molecular dynamics. For synthesized compounds the IC50 of acetylcholine esterase inhibition was about 9 X M, and for the most active the value was four to five times... 

---