Calcium channel blockers binding sites

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 ... 

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). 

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-... 

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]. 

Figure 7.12 Diagrammatic representation of cross section of calcium channel showing various sites that bind drugs and toxins. Bay K 8644, atrotoxin and maitotoxin are agonists (activators) of calcium channels. Nifedipine, verapamil, and diltiazem are antagonists (blockers) of calcium channels. (From Eldefrawi, M.E. and Eldefrawi, A.T., in Safe Insecticides Development and Use, Hodgson, E. and Kuhr, R.J., Eds., Marcel Dekker, New York, 1990, p. 155. With permission.)...

Several 1,4-dihydropyridine calcium channel blockers have been tritiated and used to investigate binding of this class of drugs. The majority of studies utilized [3H]nitrendipine [26, 87-115], but [3H]nimodipine [ 115-123], [3H]nifedipine [124] and [3H]PN 200-110 [97,106,125,126] have also been employed in some studies. Drug binding has been shown to be specific, saturable, rapid and reversible. Scatchard plots of the specific binding at equilibrium are linear, consistent with mass action behaviour. The apparent dissociation constant (A d) and the number of binding sites (Bmax) may be determined from the Scatchard plot. 

No. Binding sites for drugs of the dihydropyridine class are separate from those of other calcium channel blockers. 

Calcium channel blockers, also known as calcium antagonists, are a class of hypertension drugs that inhibit the influx of calcium ions through the cell membrane. A decrease in calcium ions results in less contraction of the cardiac and vascular muscles. There is an increase in the diameter of the arteries. This vasodilatation results in a lowering of the blood pressure. Despite their name, calcium channel blockers do not plug the hole and physically block the calcium ion channel. Rather, they bind to specific receptor sites [30]. Examples of calcium channel blockers are nifedipine (Procardia , Pfizer), nicardipine hydrochloride, amlodipine besylate sulfonate (Norvasc , Pfizer) and verapamil hydrochloride (Calan , Pfizer). Verapamil has a chiral carbon but is administered as a racemic mixture. 

Conotoxin-GS, a sodium channel blocker isolated from C. geographus, has the 6-Cys/4-loop framework (C—C—CC—-C—C) of co-conotoxins rather than the 6-Cys/3-loop arrangement (CC—C—C—CC) of the p-conotoxins, the major Na channel blocker from C. geographus (Yanagawa et al., 1988). Conotoxin-GS also has the conserved Gly residue in the first loop typical of co-conotoxins. In fact, Yanagawa and co-workers have pointed out the greater sequence similarity of conotoxin-GS to the calcium channel blocker co-conotoxin MVIIA than to the p-conotoxin GUI series. Although the affinity of conotoxin-GS to sodium channels is much less than that of p-conotoxins, conotoxin-GS was also found to preferentially bind to Site I of the muscle rather than the neuronal subtype of sodium channels. 

One of the characteristics of protein calcium channels is their sensitivity to ablock by transition metal cations. Lanthanum is a particularly potent blocker. It is suggested that permeant and blocking ions compete for the common binding sites in the channels. The PolyP-PHB channel complexes are also blocked by transition metal cations in a concentration-dependent manner. A nearly complete block of single-channel currents was observed in the synthetic complexes at concentations > 0.1 mM La3+ (0.1 % of Ca2+) (Das et al., 1997). Evidently, PHB-PolyP complexes are versatile ion carriers whose selectivities may be modulated by small adjustments of the local pH. The results may be relevant to the physiological function of PHB-PolyP channels in bacteria and the role of PHBs and PolyPs in the Streptomyces lividans potassium channel (Das and Reusch, 2001). 

The specific Ca channel antagoni.sts verapamil, nifedipine, and diltiazem interact at specific sites on the calcium channel protein. These blockers do not occlude the channel physically but bind to sites in the channel, as they can promote both channel activation and antagonism. AITiniiy fix binding sites on the channel varies, depending un the status of the channel. The channel can exist in either an open (0. re.sting (R). or inactivated (I) state, and the equilibrium lx-, tween them is determined by stimulus frequency and mem-... 

In clinical practice, there Is further selectivity of drug action at the L-channels, in part originating from the fact that there seem to be separate, but adjacent, binding sites for different chemical classes of calcium antagonists. Of the L-channel blockers, some chemical families are more active on the smooth muscle of the cardiovascular system (e.g. nifedipine and most other DHPs), whereas others are more cardioactive (e.g. verapamii). Some further details of these... 

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