Nifedipine binding site

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... 

This does not mean that they have a common site of action. For instance, the inorganic inhibitors - Mn +, Ni +and Co2+ - act at the outer surface of the cell membrane, where they compete with Ca + for binding sites (34,54). By contrast the organic inhibitors - eg. verapamil, D-600 appear to act at the cytosolic surface (55,56). Even the organic inhibitors differ in their precise mode of action. For example, nifedipine (46) reduces the number of channels that are operational at a given time without altering the kinetics of channel activation or inactivation, whereas verapamil (17) alters the kinetics of channel reactivation so that recovery is delayed after a prior period of activity. Possibly this effect of verapamil is associated with its ability to displace Ca2+ from superficially located binding sites (47). 

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. 

Piroxicam may displace highly protein-bound drugs from binding sites. Toxicity may occur with coumarin derivatives, phenytoin, verapamil, or nifedipine. Increased nephrotoxicity may occur with gold compounds, other... 

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.)...

On the other hand, DHPs can be activators (i.e.. Bay K 8644) or inhibitors (i.e., nifedipine or nitrendipine) and, therefore, are thought to act allosterically to shift the channel toward the open or closed state, rather than by occluding the ion-conducting pore. Their receptor sites consist of amino acids located in the S6 segments of domains III and IV and the S5 segment of domain III [108,110,111]. Interestingly, the DHP receptor site shares some common amino acids with the PAA receptor site. Finally, BTZs (diltiazem and related compounds) bind to a third receptor site, but the amino acids that are required for their interaction overlap also those required for PAA binding [112,113]. 

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. 

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