Nicotine agonists, similarity

Most of the direct organ system effects of muscarinic cholinoceptor stimulants are readily predicted from a knowledge of the effects of parasympathetic nerve stimulation (see Table 6-3) and the distribution of muscarinic receptors. Effects of a typical agent such as acetylcholine are listed in Table 7-3. The effects of nicotinic agonists are similarly predictable from a knowledge of the physiology of the autonomic ganglia and skeletal muscle motor end plate. 

The nicotinic receptors on the neuromuscular end plate apparatus are similar but not identical to the receptors in the autonomic ganglia (Table 7-1). Both types respond to acetylcholine and nicotine. (However, as noted in Chapter 8, the receptors differ in their structural requirements for nicotinic blocking drugs.) When a nicotinic agonist is applied directly (by iontophoresis or by intra-arterial injection), an immediate depolarization of the end plate results, caused by an... 

Carbachol Nonselective muscarinic and nicotinic agonist otherwise similar to bethanechol used topically almost exclusively for glaucoma ... 

Arteca, G.A., Jammal, V.B., Mezey, P.G., Yadav, J.S., Hermsmeier, M.A. and Gund, T.M. (1988b). Shape Group Studies of Molecular Similarity Relative Shapes of Van der Waals and Electrostatic Potential Surfaces of Nicotinic Agonists. J.Mol.Graphics, 6,45-53. 

Cholinergic Antagonists. Atropine, which is a muscarinic antagonist that in some cases also blocks the effects of nicotinic agonists, suppresses REM sleep. The effects of the muscariniclnicotinic agonist carbachol, which facilitates REM sleep, are prevented by systemic administration of atropine. Similarly, scopolamine delays the appearance of REM sleep (35). 

III. C>f these, type II is the most common (10% of neurons in primary culture) and may correspond to a4j32. It is very sensitive to dihydro-jS-erythroidine (10 nM) and is decreased by high concentrations of methyllycaconitine (100 nM). It is also blocked by mecamylamine (I fxM). The most rare and slow responses were termed type III (2%of hippocampal neurons in culture) these may correspond to o 3j34 receptors, are sensitive to I fiM-mecamylamine or 20 ixM tubocurarine, and resistant to 100 nM methyllycaconitine. This classification is likely to hold outside the hippocampus as well, as shown by results in normal and 32-knockout mice [see, for instance, Zoli et al. (212), who distinguish a fourth type of nicotinic response, similar to type III, but with faster desensitization at high nicotine doses and different properties in equilibrium binding assays with agonists]. 

In addition, Kihara et al. (1997) showed that the novel al nicotinic agonist anabaseine derivative DMXB produced a similar effect. Thus, the potential cytoprotec-tive effects of nicotine appear to be receptor-mediated, suggesting the possibility that novel nicotinic agonists might provide more potent effects. 

Arteca GA, Jammal YB, Mezey PG, Yadav JS, Hermsmeiers MA, Gund TM. Shape group studies of molecular similarity relative shapes of van der Waals and electrostatic potential surfaces of nicotinic agonists. J Mol Graph 1988 6 45-53. 

Certain evidence suggests that histrionicotoxin in a stimulus-dependent manner converts the receptor-channel complex to a state similar if not identical with the so-called desensitized state. Certainly the presence of low concentrations of histrionicotoxins increases the nicotinic agonist-elicited phenomenon known as desensitization (48). In addition, the presence of histrionicotoxin, like classical desensitization, increases the apparent affinity of nicotinic agonists for the receptors 48,154,155). In one study, in electroplax membranes, synthetic dl-perhydrohistrionicotoxin was reported to have no significant effect on desensitization processes 98). Further studies will be needed to fully define the mechanism of action of histrionicotoxins on acetylcholine receptor channel complexes and to determine whether these alkaloids also interact with other chemosensitive channels. 

Some agonists, such as methacholine, carbachol and bethanecol are structurally very similar to ACh (Fig. 6.6). They are all more resistant to attack by cholinesterase than ACh and so longer acting, especially the non-acetylated carbamyl derivatives carbachol and bethanecol. Carbachol retains both nicotinic and muscarinic effects but the presence of a methyl (CH3) group on the p carbon of choline, as in methacholine and bethanecol, restricts activity to muscarinic receptors. Being charged lipophobic compounds they do not enter the CNS but produce powerful peripheral parasympathetic effects which are occasionally used clinically, i.e. to stimulate the gut or bladder. 

Acetyichoiine Lobeline acts as a partial agonist at nicotinic receptors. It displaces nicotine with a low nanomolar affinity in the rat brain (Damaj et al. 1997). Similar to nicotine, it may act as an antagonist through persistent activation and desensitization of the receptor (Briggs and McKenna 1998 Tani et al. 1998). Lobeline shows a greater affinity for the pZ subunit of the nicotinic receptor than jS4 subunits (Parker et al. 1989). 

Sir Henry Dale noticed that the different esters of choline elicited responses in isolated organ preparations which were similar to those seen following the application of either of the natural substances muscarine (from poisonous toadstools) or nicotine. This led Dale to conclude that, in the appropriate organs, acetylcholine could act on either muscarinic or nicotinic receptors. Later it was found that the effects of muscarine and nicotine could be blocked by atropine and tubocurarine, respectively. Further studies showed that these receptors differed not only in their molecular structure but also in the ways in which they brought about their physiological responses once the receptor has been stimulated by an agonist. Thus nicotinic receptors were found to be linked directly to an ion channel and their activation always caused a rapid increase in cellular permeability to sodium and potassium ions. Conversely, the responses to muscarinic receptor stimulation were slower and involved the activation of a second messenger system which was linked to the receptor by G-proteins. 

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