Ca2- antagonists

Not all cells in the heart express the fast sodium channel. Thus, sinus nodal and atrioventricular nodal cells lack the fast Na+ channel and instead generate their action potentials via opening of Ca2+ channels. This is the basis for their sensitivity to Ca2+ antagonists. 

At present, only organic blockers of L-type Ca2+ channels (also termed Ca2+ antagonist ) are licensed... 

In the case of L-type Ca2+ channels, they also carry binding sites for Ca2+ antagonist drugs. The accessory a2-5, p, and y subunits stabilize Ca2+ channel function and support its targeting to the plasma membrane. Notably other proteins can associate with the channel complex allowing the formation of signaling complex important for channel targeting and modulation. 

Abernethy DR, Schwartz JB (1999) Ca2+-antagonist drags. N Engl JMed 341 1447-1457... 

SADP or sulfo-SADP also have been used to study the phenylalanine-methionine-arginine-phenylalanine-amide-activated sodium channel (Coscoy et al., 1998), various apolipoprotein E isoforms (Mann et al., 1995), the high-affinity phenylalkylamine Ca2+ antagonist binding protein from guinea pig (Moebius et al., 1994), the interaction of non-histone proteins with nucleosome core particles (Reeves and Nissen, 1993), and the interactions among cytochromes P-450 in the endoplasmic reticulum (Alston et al., 1991). See Chapter 28 for methods of using photoreactive heterobifunctional crosslinkers to study protein interactions. 

Moebius, F.F., Hanner, M., Knaus, H.G., Weber, F., Striessnig, J., and Glossmann, H. (1994) Purification and amino-terminal sequencing of the high affinity phenylalkylamine Ca2+ antagonist binding protein from guinea pig liver endoplasmic reticulum./. Biol. Chem. 269, 29314-29320. 

Recently, two groups (29,95) reported that Ca2+ antagonists (D 600, cinnar-izine, verapamil) inhibit 3H-PCP binding to its specific sites with Kj ranging between 0.1 and 2 nM. Furthermore, the cations La3+ and Co2+, which are known blockers of the Ca2+ channel, also inhibit the specific binding of... 

PCP dependence, treatment of, 31 PCP poisoning, in children, 30 PCP-type hallucinogens, structural relationship of, 26 3H-PCP, binding sites for effect of Ca2+ antagonists on, 150-151... 

Maier I, Calenberg M (1994) Effect of extracellular Ca2+ and Ca2+ antagonists on the movement and chemoorientation of male gametes of Ectocarpus siliculosus (Phaeophyceae). Bot Acta 107 451 160... 

Hot plate Mouse Fentanyl Dihydro- pyridines (DHPs) F i.v. DHPs i.v. F antinociceptive effects are potentiated by simultaneous i.v. administration of the Ca2+ antagonists Hoffmeister and Tettenborn (1986)... 

Ca2+-antagonists are able to enhance the antinociceptive effect of opioids... 

Hall and Wolf [217] have proposed a hypothesis, concerning the pathogenesis of post-traumatic central nervous system ischaemia, which integrates an injury-induced rise in intracellular Ca2+, the increased synthesis of vasoactive prostanoids and progressive microvascular lipid peroxidation. The model used anaesthetised cats with a contusion injury to the lumbar spinal cord. Antioxidants, vitamin E and selenium, were compared with various Ca2 + antagonists, cyclo-oxygenase inhibitors, a thromboxane synthetase inhibitor and the stable prostacyclin analogue. The most impressive preservation of post-traumatic spinal cord blood flow was provided by the antioxidants. 

Tab. 4.34 Partition coefficients of Ca2+ antagonists in synaptic plasma membranes (SPM) and liposomes and octanol-water, at 25 °C. (Reprinted from Tab. 1 of ref. 122 with permission from Elsevier Science)...

With the exception of S-metolachlor, all the molecules listed under the column Final Target are used in pharmaceutical formulations. Dilitiazem is a Ca2+ antagonist, while Cilazapril is an angiotensin-converting enzyme inhibitor. Levofloxacin is an antibacterial, and cilastatin is used as an in vivo stabilizer of the antibiotic imipenem. S-metolachlor is a herbicide sold under the trade name of DUAL MAGNUM. Although the structures of the final targets are more complex than those of the intermediates, enantioselective syntheses of the intermediates are the most crucial steps in the complex synthetic schemes of these molecules. 

Calcium antagonists (slow channel blockers, slow Ca2+ antagonists) are a heterogeneous group of substances with widely differing tissue specificities, potency and properties. Some of them exhibit other properties in addition to that of Ca + antagonism. 

Figure 1. Structural formulas of some Ca2+ antagonists and their derivatives.

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