Calcium channel blockers binding

Calcium channel blockers bind specifically to receptor sites associated with the voltage-dependent calcium channels [31,32]. These blockers inhibit calcium uptake [33,34] and block smooth muscle contraction [35,36]. All these three activities of calcium channel blockers have been found to be mutually correlated. For ten known calciiun channel blockers (Table 4), Papaionnou et al. [37] derived the correlations ... 

Do all classes of calcium channel blocker bind to the same receptor on the channel ... 

Batra S (1990) Interaction of antiestrogens with binding sites for muscarinic cholinergic drugs and calcium channel blockers in cell membranes. Cancer Chemother Pharmacol 26 310-312... 

For example, in the case of compound XX, which among other activities has an IC50 of 60 nM on the calcium channel diltiazem site binding assay, a search for BioPrint compounds with an activity in the similar range yields a series of compounds nearly all of which are known calcium channel blockers (see Table 2.1). 

DC028 Thuleau, P., A. Graziana, R. Ranjeva, and J. I. Schroeder. Solubilized proteins from carrot Daucus carota L.) membranes bind calcium channel blockers and form calcium-permeable ion channels. Proc Nat Acad Sci (USA) 1993 90 765-769. 

The calcium channel blockers are orally active agents and are characterized by high first-pass effect, high plasma protein binding, and extensive metabolism. Verapamil and diltiazem are also used by the intravenous route. 

Sodium and potassium are not the only ions which can participate in pumps and channels. Calcium is also pumped, channeled, exhanged,and stored. See Figure 23. Calcium concentration within the cell cytoplasm is very low. This allows the calcium to play a pivotal role in cellular activity. The cytoplasmic protein calmodulin binds and stores calcium ion. Various intracellular structures and organelles such as the mitochondria and sarcoplasmic reticulum also store calcium. Calcium is vital to such functions as the release of neurotransmitters from nerve cells. There are at least seven known modes of biochemical action for this ion, one of the most important of which involves stimulation of cardiac muscle protein (actin-myosin). Certain types of angina (heart pain) are believed to be caused by abnormal stimulation of cardiac arteries and muscle (coronary spasm) A relatively new class of drugs, known as the calcium channel blockers, has brought relief from pain and arrhythmias (irregular heart beats). 

Beta-blockers block norepinephrine and epinephrine from binding to beta-adrenoceptors and a calcium channel blocker inhibits the flow of calcium ions into muscles. Both slow down and relax the heart. 

Class IV drugs have a selective ability to block calcium entry into myocardial and vascular smooth-muscle cells. These drugs inhibit calcium influx by binding to specific channels in the cell membrane.12,15 As discussed previously, calcium entry plays an important role in the generation of the cardiac action potential, especially during phase 2. By inhibiting calcium influx into myocardial cells, calcium channel blockers can alter the excitability and conduction of cardiac tissues. 

The (—) isomer of the L-type calcium channel blocker (+)-niguldipine is dexniguldipine. This agent binds to an intracellular domain of P-gp with a K, of 10 nm. In addition, this compound can block RNA synthesis at 5 pM and possesses some anticancer activity (302). Currently, only a few studies have been conducted to evaluate the use of this compound as a P-gp modulator. Definitive results are yet to be reported. 

However, there have been some contradictory results. It has been reported that some modifiers do not compete with the cytotoxic agent for binding to P-gp even though they act as substrates for it [77]. In some resistant cell tines there was no correlation between an increase in MDR and the P-gp levels [79-81], The calcium channel blocker SR3357 (2) - which is 4—5 times more potent than verapamil - was shown not to compete for the binding site of the labeled [3H]-azidopine on P-gp whereas verapamil did. SR3357 did not bind to P-gp, but to a 65-kDa protein. Inter-... 

Tolins JP, Raij L (1990) Comparison of converting enzyme inhibitor and calcium channel blocker in hypertensive glomerular injury. Hypertension 10 452-461 Tonshoff B, Powell DR, Zhao D et al. (1997) Decreased hepatic insulin-like growth factor (IGF)-I and increased IGF binding protein-1 and -2 gene expression in experimental uremia. Endocrinology 138 938-946... 

Some members of calcium channel blockers, such as nicardipine (40) and ni-modipine (41), were identified as potent MDR antagonists. This early work stressed the lack of correlation between the calcium channel blocking and anti-MDR potencies [75]. It has been reported that DHPs bind to a site that is allosterically coupled to the receptor site which binds anticancer agents and other MDR reversal agents [76,77]. DHPs are well recognized as privileged structure for their multi-receptor affinity [78,79]. 

The library was tested using a known competition assay (142), and binding activities for the 30 pools were acquired. While the pool complexity was low, as was therefore the possibility of false positives/artifacts, the extreme similarity of all the library components with known calcium channel blockers (compare the monomers in Fig. 7.19 leading to nifedipine. Mi = A, M2 = K, M3 = T, with all the others) meant a constant level of activity was to be expected for all pools. For such a small focused library, parallel synthesis would probably have been more suitable to acquire a refined SAR, but we will see how iterative deconvolution succeeded anyway in both identifying active individuals and showing significant activity differences for different pools. The screening results are reported in Table 7.1. Five pools showed activity > 1 xM, 12 pools had an activity between 100 nM and 1 xM, and 11 pools were active between 10 and 100 nM. Two pools showed an activity around 7-8 nM They both contained methyl acetoacetate (M2, K) as well as 2-fluorobenzaldehyde (M3, P) and 2-nitroben-zaldehyde (M3, T), respectively. 

CALCIUM CHANNEL BLOCKERS ANION EXCHANGE RESINS Colestipol 1 diltiazem levels Colestipol binds diltiazem in the intestine Monitor for poor response to diltiazem. Separating doses of diltiazem and colestipol does not seem to 1 this interaction... 

RX 783006 DAMGO. ryanodine is an alkaloid from Ryania speciosa (Flacourtiaceae). It has been used as an INSECTICIDE, but is now superseded. It is a calcium-transport blocker, binding to intracellular receptor channels in the endoplasmic reticulum. It is used as a pharmacological tool. 

Goll A, Glossmann H, Mannhold R. Correlation between the negative inotropic potency and binding parameters of 1,4-dihydropyridine and phenylalkylamine calcium channel blockers in cat heart. Naunyn Schmiedebergs Arch Pharmacol 1986 334 303-12. 

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