Phenylalkylamines, calcium channel

Verapamil is a phenylalkylamine calcium channel blocker, with actions mainly on the heart. 

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. 

What could be the molecular basis for the differential effects of the L-type CCBs in recurrent affective illness The more lipophilic dihydropyridine CCBs appear to act at a site within the L-type calcium channel, whereas verapamil and related phenylalkylamine CCBs appear to act on a site at the outer membranous edge of the channel [as reviewed by Janis and Triggle 1991 Triggle 1992]. Our initial clinical observations suggest the possibility that this differential biochemical mechanism of action could have differential behavioral and clinical effects. This possibility is supported by a variety of data indicating that the two classes of L-type CCBs have very different effects on biochemistry and behavior in other systems (Table 6-4], most nota-... 

Guggino, S.E., LaJeunesse, D., Wagner, J.A., et al. (1989) Bone remodeling signaled by a dihydropyridine- and phenylalkylamine-sensitive calcium channel. Proceedings of the National Academy of Science 8 2957-2960... 

The three principal structural classes of compounds have been found to bind with the L subclass calcium channel, and they are phenylalkylamines, 1,4-dihydropyridines, and the benzothiazepines, of which the protypical rep-... 

Calcium is involved in the contraction of cardiac and vascular smooth muscle cells, and in the auto-maticity of cardiac pacemaker cells. Actions of calcium channel blockers on vascular smooth muscle cells are described with the main account of these drugs in Chapter 23. Although the three classes of calcium channel blocker have similar effects on vascular smooth muscle in the arterial tree, their cardiac actions differ. The phenylalkylamine, verapamil, depresses myocardial contraction more than the others, and both verapamil and the benzothiazepine, diltiazem, slow conduction in the SA and AV nodes. 

Cayl channels (L-type) are targets of calcium-channel blockers or calcium antagonists which decrease the influx of Ca + in cardiac and smooth muscle vascular cells dihy-dropyridines (nifedipine and analogs), phenylalkylamines (verapamil) and benzothiazepines (diltiazem), widely used as antihypertensive, antianginal and antiarrhythmic drugs. Cayl openers, like Bay K 8644, have been synthesized but have not found any therapeutic interest. 

There are approximately a dozen calcium channel antagonists marketed in the United States for the treatment of hypertension, certain dysrhythmias, and some forms of angina (see Chaps. 13,15, and 17). The calcium channel blockers are classified by their chemical structure as phenylalkylamines (e.g., verapamil), benzothiapines (e.g., diltiazem), and dihydropyridines (e.g., amlodipine, felodipine, nicardipine, and nifedipine). Several of these agents, namely, diltiazem, nicardipine, nifedipine, and verapamil, are formulated as sustained-release oral dosage forms or have a slow onset of action and longer half-life (e.g., amlodipine " ), allowing once-daily administration. 

L-type or high-voltage-activated calcium channels carry the majority of the calcium inward current in smooth muscle cells. They start to activate at a high membrane potential (around -30 mV) with a maximum at slightly positive membrane potentials (around -f-10 mV), have a large conductance (20-25 pS with 110 mM Ba2+ as charge carrier), inactivate slowly, and are readily and specifically blocked by the classic organic calcium channel blockers nifedipine (a 1,4-dihydro-pyridine), verapamil (a phenylalkylamine), and dil-tiazem (a benzothiazepine) (see Hofmann etah, 1994). 

Calcium-entry blockers include those agents that are selective for slow calcium channels in the myocardium (slow channel blockers) and consist of the following categories of substances benzothiazepines (diltiazem and dihydropy-ridines)—nifedipine, nicardipine, niludipine, nimodipine, nisoldipine, nitrendipine, ryosidine, amlodipine, azodipine, dazodipine, felodipine, flordipine, iodipine, isradipine, mesu-dipine, oxodipine, and riodipine and, phenylalkylamines— verapamil, gallopamil, anipamil, desmethoxyverapamil, emopamil, falipamil, and ronipamil. 

Motoike HK, Bodi I, Nakayama H, Schwartz A, Varadi G. A region in IVS5 of the human cardiac L-type calcium channel is required for the use-dependent block by phenylalkylamines and benzothiaz-epines. 7 Sio/ Chem 1999 274(14) 9409-20. 

Phenylalkylamine receptors are located somewhere near the S6 helix and around C-terminal chain of the four domains of the subunit in the calcium channel. In contrast to benzothiazepines, the binding of phenylalkyl-amines to their receptor will prevent binding of a DHP to its receptor. Table 11.2 surmnarises the characteristics of the three drug types. 

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