Calcium channel antagonistic

Dreyer EB, Kaiser PK, Offermann JT, Lipton SA (1990) HIV-1 coat protein neurotoxicity prevented by calcium channel antagonists. Science 248(4953) 364-367 Dreyer EB, Zurakowski D, Gorla M, Vorwerk CK, Lipton SA (1999) The contribution of various NOS gene products to HlV-1 coat protein (gpl20)-mediated retinal ganglion cell injury. Invest Ophthalmol Vis Sci 40(5) 983-989... 

The P-blockers propranolol and timolol are FDA-approved for migraine prophylaxis, but other drugs in the class are also as effective.46 Cautious dosage titration is advised for those patients who do not have other indications for P-blocker use. Rizatriptan interacts with propranolol and thus dosages must be titrated downward, or another triptan chosen for abortive therapy.36 Comorbid reactive airway disease is a relative contraindication to P-blocker prophylaxis, and patients with cardiac conduction disturbances should be closely monitored. Calcium channel antagonists are often used when patients cannot tolerate P-blockers. They are purported to beneficially... 

Franke, U. Munk, A. Wiese, M., Ionization constants and distribution coefficients of phenothiazines and calcium channel antagonists determined by a pH-metric method and correlation with calculated partition coefficients, J. Pharm. Sci. 88, 89-95... 

Bauerle, H.-D. Seelig, J., Interaction of charged and uncharged calcium channel antagonists with phospholipid membranes. Binding equilibrium, binding enthalpy, and membrane location, Biochemistry 30, 7203-7211 (1991). 

Mason, R. R Campbell, S. F. Wang, S.-D. Herbette, L. G., Comparison of location and binding for the positively charged 1,4-dihydropyridine calcium channel antagonist amlopidine with uncharged drugs of this class in cardiac membranes, Molec. Pharmacol. 36, 634—640 (1989). 

JW Huff, PS Reinach. (1985). Mechanism of inhibition of net ion transport across frog corneal epithelium by calcium channel antagonists. J Membr Biol 85 215-223. 

Potential central nervous system indications for calcium channel antagonists... 

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. 

A structurally diverse array of N-type calcium channel antagonists has been reported, and two recent extensive reviews have summarized the structures and associated data through 2008 [59,60]. Among these... 

Type IV drugs inhibit calcium entry into the cell, which slows conduction, prolongs refractoriness, and decreases SA and AV nodal automaticity. Calcium channel antagonists are effective for automatic or reentrant tachycardias that arise from or use the SA or AV nodes. 

If /1-blockers are ineffective or not tolerated, then monotherapy with a calcium channel antagonist or combination therapy may be instituted. Reflex tachycardia from nitrates can be blunted with /1-blocker therapy, making this a useful combination. Patients with severe angina, rest angina,... 

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