Transmembrane channel design

The site of action on the Na-i- channel for cocaine and its analogs appears to be on the intracellular side of the channel, so cocaine must evidently cross the cell membrane to be effective (Narahashi and Frazier 1971). The Na-i- channel is composed of a large protein divided into a, (31, and (32 subunits. The a subunit is further divided into four domains, each of which contains four transmembrane segments (designated I-IV). 

The chemistry of transport systems has three main goals to design transport effectors, to devise transport processes, and to investigate their applications in chemistry and in biology. Selective membrane permeability may be induced either by carrier molecules or by transmembrane channels (Fig. 10). 

Ions and small molecules may be transported across cell membranes or lipid bilayers by artificial methods that employ either a carrier or channel mechanism. The former mechanism is worthy of brief investigation as it has several ramifications in the design of selectivity filters in artificial transmembrane channels. To date there are few examples where transmembrane studies have been carried out on artificial transporters. The channel mechanism is much more amenable to analysis by traditional biological techniques, such as planar bilayer and patch clamp methods, so perhaps it is not surprising that more work has been done to model transmembrane channels. 

The TRPV receptor contains six transmembrane domains designated S1-S6. These domains anchor the channel to the cellular membrane. Between S5 and S6 there is a pore. TRPV possess three ankyrin repeats. This transmembrane protein has an extracellular surface and an intracellular surface (Figure 128.3). Factors that activate and regulate this channel act in different domains. Antagonists of this channel may act in different areas of the complex molecule, the pore, the capsaicin site, the extracellular area, or the intracellular area, leading to its inactivation. 

Liu et al. [14] functionalized DWCNTs as artificial water channel proteins. For the first time, molecular dynamics simulations showed that the bilayer structure of DWCNTs is advantageous for CNT-based transmembrane channels. Shielding of the amphiphilic outer layer could guarantee biocompatibility of the synthetic channel and protect the inner tube (functional part) from disturbance of the membrane environment. This novel design could promote more sophisticated nanobiodevices, which could function in a bioenvironment with high biocompatibility. 

Classes I, III, and IV all involve transmembrane ion channels Classes I and III involve Na+ channels. Class I compounds are designed to block cardiac Na channels in a voltage-dependent manner, similar to local anesthetics. Not surprisingly, many of these Class I agents are either local anesthetics or are structurally based on local anesthetics. Class I compounds include procainamide (7.15), disopyramide (7.16), amiodarone (7.17), lido-caine (7.5), tocainide (7.18), mexiletine (7.19), and flecainide (7.20). The majority of these compounds possess two or three of the fundamental structural building blocks found within local anesthetics. Propranolol (7.21) is the prototypic Class II agent. Class III compounds include molecules that block outward K channels, such as sotalol (7.22) and dofetilide (7.23), and molecules that enhance an inward Na current, such as... 

Figure 14. A general view of the designed transporter, which is composed of three units. The "core" unit lying near the bilayer mid-p a ie with "wall" units radiating from it. The core unit provides a rigid framework to direct the wall units to the face of the bilayer. The wall units are stiff to provide structural control, and incorporate both the polar and nonpolar functionality (Y, Z) required for a channel. The structure is completed with hydrophilic "head" groups (X) to provide overall amphiphilic character and to assist in the transmembrane orientation of the molecule.

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