Selectivity nAChR

The open channel has in most cases a selective permeability, allowing a restricted class of ions to flow,for example Na+, K+, Ca++ or Cl- and, accordingly, these channels are called Na+-channels, K+-channels, Ca -channels and Cr-channels. In contrast, cation-permeable channels with little selectivity reject all anions but discriminate little among small cations. Little is known about the structures and functions of these non-selective cation channels [1], and so far only one of them, the nicotinic acetylcholine receptor (nAChR, see Nicotinic Receptors), has been characterized in depth [2, 3]. The nAChR is a ligand-gated channel (see below) that does not select well among cations the channel is even permeable to choline, glycine ethylester and tris buffer cations. A number of other plasma... 

Non-selective Cation Channels. Figure 1 The nicotinic acetylcholine receptor (nAChR) is localized within the cell membrane above the cell membrane is the synaptic cleft, below the cytoplasm. Drawing of the closed (left) and open (right) nAChR showing acetylcholine (ACh) binding and cation movement. Dimensions of the receptor were taken from references [2, 3]. 

The regions involved in the cation vs. anion selectivity are not well defined, as they are for the nAChR. However, in contrast to the nAChR, the residues within the pore contribute to the selectivity, as receptors formed from fully edited AMPA or kainate receptors (e.g., having an R at the Q/R site) are also permeable to chloride. 

The nAChR subtypes vary in response to pharmacological manipulation. The a7 receptors have a low affinity for nicotine and are sensitive to a-bungarotoxin (a-BTX) antagonism, whereas the heteromeric nAChRs are not.14 The p2 containing (p2 asterisk denotes the presence of additional subunits) nAChRs have the highest affinity for nicotine binding and some selectivity for antagonism... 

Inhaled nicotine is efficiently delivered to the brain (see chapter by Benowitz, this volume) where it selectively interacts with its central targets, the neuronal nicotinic acetylcholine receptors (nAChRs). The multiple subtypes of uAChR (see chapter by Collins et al, this volume) all bind nicotine but with different affinities, depending on the subunit composition of the uAChR. Binding may result in activation or desensitisation of uAChRs, reflecting the temporal characteristics of nicotine dehvery and local concentration of nicotine. Another level of complexity of the actions of nicotine reflects the widespread and non-uniform distribution of uAChR subtypes within the brain, such that nicotine can influence many centrally regulated functions in addition to the reward systems. In this chapter, we address the consequences of nicotine interactions with nAChRs at the molecular, cellular and anatomical levels. We critically evaluate experimental approaches, with respect to their relevance to human smoking, and contrast the acute and chronic effects of nicotine. 

Cytisine (30), from Cytisus scoparius L., has been found to be a selective and specific probe for the nicotinic-type acetylcholine receptor (nAChR) as a partial agonist and has served as the lead compound... 

Preparation and Evaluation of the nAChR-Enriched Plasma Membranes as a Target for the In Vitro Selection Process... 

Selection of Aptamers that Bind to the nAChR and Displace Cocaine... 

Phenol- and chloroform-extract and ethanol precipitate the recovered RNA (see Subheading 3.7). The RNA is reverse transcribed, purified, and precipitated as detailed in Subheadings 3.6 (25) and 3.7, and then RNA is used for the nitrocellulose filter selection step and cocaine displacement of nAChR-bound RNA molecules (Fig. 2). 

Screening for biological activity The biological activity of the selected RNA aptamers are determined in vitro, as to whether they inhibit the nAChR function as cocaine does or whether they compete with cocaine but do not have any biological activity by themselves and, therefore, protect the receptor against inhibition by cocaine (25). 

The beneficial effects of ChCMs are many. Nicotine has been reported to enhance cognition, increase attention, reduce anxiety, decrease nociceptive perceptions, and act as a neuroprotectant.37 However, the liabilities associated are significant as nicotine causes decreased body temperature, reduction of locomotor activity, and induction of seizures.37 Nicotine also possesses a drug discrimination or cue upon administration.37 These benefits and liabilities show the diversity of nAChRs and the potential for defining each pharmacological effect with selective agents. 

Epibatidine s antinociceptive effect can be antagonized by pretreatment with the centrally active nAChR antagonist mecamylamine, but not with the peripheral antagonist hexamethonium, so the activation of central nAChRs is presumed to be essential for nicotinic analgesics (Sullivan et al., 1994). The high toxicity of epibatidine has been attributed to its lack of selectivity for specific neuronal nAChR subtypes and has precluded its development as a therapeutic agent. 

Epibatidine was shown to be a very potent and selective agonistic ligand of nicotinic acetylcholine receptors. This natural product is effective in various animal models of pain through a pronounced nAChR agonistic mechanism (Ki <100 pm) which is accompanied by severe and nACh-related side-effects (Corey et al. 1993 Rupniak et al., 1994 Boyce et al., 2000). A clear differentiation between antinociceptive activity in animal models of pain and toxic side-effects cannot be determined. Nevertheless there is some activity directed towards the development of epibatidine as an analgesic (Bai et al., 1997). 

The competition for nAChR binding by acetylcholine and nicotine illustrates the key role of selectivity in binding in supramolecular chemistry. Because nAChR is not fully selective, it is also able to bind the interfering nicotine. The fact that nicotine, like acetylcholine, possesses a quaternary ammonium moiety that is implicated in its binding mechanism highlights the dependence of biological processes on ostensibly weak supramolecular interactions. 

Tropisetron (a selective 5-HT3R antagonist, Fig. 1) has been found to be also a potent and selective but partial agonist of a7-nAChR thus potentially effecting learning and memory processes [39], Clinical implications and use are still not elaborated. 

Tropisetron is a synthetic TTA containing an esterified tropine moiety (Fig. 1). This drug is a potent antiemetic selective 5-HT3 receptor antagonist to treat postoperative and chemotherapy-induced vomiting and nausea by daily intravenous or oral administration [70], Furthermore, tropisetron is a potent and selective partial agonist of a7-nAChR [39],... 

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