Calcium channels selectivity

Opiates iateract with three principal classes of opioid GPCRs )J.-selective for the endorphiQS,5-selective for enkephalins, and K-selective for dynorphias (51). AU. three receptors have been cloned. Each inhibits adenylate cyclase, can activate potassium channels, and inhibit A/-type calcium channels. The classical opiates, morphine and its antagonists naloxone (144) and naltrexone (145), have moderate selectivity for the. -receptor. Pharmacological evidence suggests that there are two subtypes of the. -receptor and three subtypes each of the 5- and K-receptor. An s-opiate receptor may also exist. 

Some metals, such as cadmium, cobalt, and lead, are selectively car-diotoxic. They depress contractivity and slow down conduction in the cardiac-system. They may also cause morphological alterations, e.g., cobalt, which was once used to prevent excessive foam formation in beers, caused cardiomyopathy among heavy beer drinkers. Some of the metals also block ion channels in myocytes. Manganese and nickel block calcium channels, whereas barium is a strong inducer of cardiac arrhythmia. 

The selectivity of another cellulose-based CSP, Chiralcel OJ, has also been examined in SFC [60]. Separations of racemic drugs such as benoxaprofen, temazepam, and mephobarbital were obtained. Acetonitrile proved to be a better modifier than methanol for some of the compounds investigated. The four optical isomers of a calcium channel blocker were resolved by Siret et al. on the Chiralcel OJ CSP [30]. In LC, two CSPs were required to perform the same separation. 

HVA calcium channels are biochemically hetero-oligomeric complexes of five proteins encoded by four gene families (Fig. 1) The ax subunits of 190-250 kDa contain the voltage-sensor, the selectivity filter, the ion-conducting pore, the binding sites for most calcium... 

Voltage-dependent Ca2+ Channels. Figure 2 Subunit composition of a HVA calcium channel. The selectivity filter of the channel is created by four glutamates (E). 

As described in the previous section, calcium channel blockers should not be administered to most patients with ACS. Their role is a second-line treatment for patients with certain contraindications to P-blockers and those with continued ischemia despite P-blocker and nitrate therapy. Administration of either amlodipine, diltiazem, or verapamil is preferred.2 Agent selection is based on heart rate and left ventricular dysfunction (diltiazem and verapamil are contraindicated in patients with bradycardia, heart block, or systolic heart failure). Dosing and contraindications are described in Table 5-2. 

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). 

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. 

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