Ion channels models

Based on the supramolecular ion channel model of 1, the combined observations suggest a mechanism for the voltage dependence as schematically shown in Figure 24 Amphiphilic molecules are assembled to constract a half-channel in each... 

Xu Z, Cai W, Cheng X Image charge method for reaction fields in a hybrid ion-channel model, Commun Comput Phys 9(4) 1056—1070, 2011. 

Newel experimental approaches to anxiety therapy include ligands interacting with the ligand-gated ion channels that are selectively activated by nicotine, C qH 4N2 (87), the well-known active ingredient of cigarettes which has anxiolytic actions (42). Cholecystokinin B receptor ligands, specifically the dipeptoid, CI-988 [130404-91 -0] 02 1142 40 (88) have demonstrated anxiolytic activity ia preclinical models (43). 

Fig. 1. Model of a ligand gated ion channel (LGIC) where (a) is the structure of a generic LGIC subunit showing the two cysteine (Cys) residues common to all LGIC subunits, and (b) shows the arrangement of five such subunits as a pentamer having psuedo-cyclic symmetry delineating a gated, fluid-filled...

II The Channel Mechanism of Ion Transport The Gramicidin Channel Model 181... 

Two-state model, a model of proteins that coexists in two states controlled by an equilibrium constant. Molecules with selective affinity for one of the states will produce a bias in that state upon binding to the system. Two-state theory was conceived to describe the function of ion channels but also has relevance to receptors (see Chapter 3.7). 

With few exceptions, information on the anticonvulsant pharmacology of specific ion channel subunits analyzed in expression systems is scarce. Hitherto, a first understanding of the mechanism of action of most antiepileptic dtugs has evolved from analyses of somatic ion channel pharmacology either in isolated neurons from human or rodent neurons, or cell culture models. 

The major drawback of these models, however, is their lack of a clear reference between model components and constituent parts of the biological system (e.g. structures like ion channels, transporter proteins, receptors, etc.). These models, therefore, do not permit the simulation of patho-physiological detail, such as the series of events that follows a reduction in oxygen supply to the cardiac muscle and, ultimately, causes serious disturbances in heart rhythm. 

Cystic fibrosis (CF) is caused by mutations in the CF transmembrane conductance regulator (CFTR), a chloride (CF) channel characterised by chloride permeability and secretion, and also by the regulation of other epithelial ion channels (Eidelman et al, 2001). Mutations in the CFTR gene lead to an impaired or absent Cl conductance in the epithelial apical membrane, which leads to defective Cl secretion and absorption across the epithelium. Genistein (Illek et al, 1995 Weinreich et al, 1997) and other flavonoids (Illek and Fisher, 1998) have been shown, in different animal and tissue models, to activate wild-type CFTR and CFTR mutants by (Eidelman et al, 2001 Roomans, 2001 Suaud et al, 2002) ... 

For targets that lack structural information, such as GPCRs or ion channels, a pharmacophore model or multiple pharmacophore models for different series of compounds can explain SAR and guide the synthesis of new analogs. Alternatively, homology models based on bacteriorhodopsin have been used to explain the interactions of small molecules with GPCRs. 

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