Muscarinic group

Two distinct receptor groups have been identified for acetylcholine, the nicotinic and the muscarinic groups (Table 11.1). Furthermore, there are at least four subtypes of nicotinic and five subtypes of muscarinic receptors. Nicotinic receptors are ubiquitous and exist at the neuromuscular junctions of skeletal muscles and on ganglion cells in the autonomic nervous system. Nicotinic receptors located on cation-specific ion channels, when opened, evoke fast, transient depolarizations of the recipient cell. Muscarinic receptors are found in smooth muscle receiving parasympathetic innervation and elsewhere, and can be blocked by atropine. Muscarinic receptors are coupled indirectly to slow and fast ion channels via G proteins. 

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. 

Because the SSRIs are derived from different chemical groups, their receptor interactions vary from compound to compound but, apart from paroxetine, none of them shows any appreciable binding to muscarinic receptors, a prime objective of their development. However, compared with other SSRIs, fluoxetine binds with moderately high affinity to human 5-HT2A (.K) 280 nM) and 5-HT2C receptors (Aij 55 nM) sertraline is a relatively potent ligand for ai-adrenoceptors, 2-adrenoceptors and Dj receptors and citalopram shows appreciable binding to 5-HTia, oc]-adrenoceptors and Hi receptors (Table 20.6 Stanford 1996). The extent to which any of these receptor interactions affects the efficacy of these compounds is not known. 

The aqueous Barbier-Grignard-type reaction has also been used in the synthesis of natural products. Chan and Li used the zinc mediated allylation as a key step in a total synthesis of (+)-muscarine (Scheme 8.5).72 The strategy was based on the observation that the diastereoselectivity of the allylation reaction in water can be reversed through the protection of the a-hydroxyl group. 

With respect to other ethnic groups, African Americans may have a differential sensitivity to weight gain on clozapine (de Leon etal, 2007). They may also require lower doses than Caucasians (Kelly et al, 2006) and inter-individual as well as ethnic responsiveness maybe partly explained by differences in dopamine receptor polymorphisms (Hwang et al, 2005). It is conceivable that side effects may also be differentially expressed based on pharmacodynamic differences resulting from polymorphisms in other receptor types (histaminergic, muscarinic, etc.). This area remains largely unexplored with respect to ethnic differences in antipsychotic side effects. 

The presence of a dichloromethylene group at the anomeric center of 82 facilitates proton abstraction at C-3 by a strong base (77), aifording the 4-deoxyglycos-3-ulose derivative 83. Reduction of the dichloromethylene group by Raney nickel gave a 1-C-methyl derivative with high stereospecificity, which opens the way to a series of 2,5-anhydro-l-deoxyalditols. Compound 83 was the key intermediate for the synthesis (78) of tosyl L-(+)-epi-muscarine (84a) and tosyl L-(+)muscarine (84b). 

EA 3167 (Fig. 43) and BZ (Fig. 44) are almost identical in structure, the former having a cyclopentyl group on the alpha carbon of the glycolic acid nucleus, while the latter has a benzyl group This minor difference seems to result in more tenacious occupancy of the muscarinic acetylcholine receptor. 

Note that it shares some structural features with the acetylcholine molecule. Specifically, both molecules possess an oxygen atom separated by two methylene (-CH2-) groups from a positively charged nitrogen atom. Muscarine was isolated from Amanita muscaria, a poisonous mushroom, more than a century ago. Muscarine causes sweating and pupillary constriction. These are some of the same effects that are caused by acetylcholine itself, confirming that muscarine is an acetylcholine agonist. 

Fig. 12.10 Distributions of three large GPCR-specific ligand groups within the Kohonen map (a) Tachykinin NKl antagonists (1400 compounds), (b) Muscarinic Ml agonists (553 compounds), (c), 63-Adrenoceptor agonists (433 compounds).

The above speculation [21] may be extended to include the related quaternary ammonium compounds such as xylocholine (XXXIX). It is probable that the volumes of the guanidinium ion and the trimethylammonium group are similar. The ionic radius of the guanidinium ion (IX) is about 3A the ionic radius of the tetramethylammonium ion has been estimated [300] to be 3-4A, although rather smaller values have also been proposed [301-303]. Crystallographic analyses of muscarine iodide [304], choline chloride [305] and acetylcholine bromide [306] have revealed that the carbon to nitrogen distance is about l-SA, and that a hydrogen bond (C-H-0 distance 2-87-3 07A) exists in the crystals of these compounds. 

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