M-cholinoceptors

Target tissues of 2"" parasympathetic neurons ACh Muscarine Atropine Muscarinic (M) cholinoceptor G-protein-coupled-receptor protein with 7 transmembrane domains... 

The choline ester, carbachol, activates M-cholinoceptors, but is not hydrolyzed by AChE. Carbachol can thus be effectively employed for local application to the eye (glaucoma) and systemic administration (bowel atonia, bladder ato-nia). The alkaloids, pilocarpine (from Pilocarpus jaborandi) and arecoline (from Areca catechu betel nut) also act as direct parasympathomimetics. As tertiary amines, they moreover exert central effects. The central effect of muscarinelike substances consists of an enlivening, mild stimulation that is probably the effect desired in betel chewing, a widespread habit in South Asia. Of this group, only pilocarpine enjoys therapeutic use, which is limited to local application to the eye in glaucoma... 

Substances acting antagonistically at the M-cholinoceptor are designated parasympatholytics (prototype the alkaloid atropine actions shown in red in the panels). Therapeutic use of these agents is complicated by their low organ selectivity. Possibilities for a targeted action include ... 

Gastric secretion. Stimulation of gastric acid production by vagal impulses involves an M-cholinoceptor subtype (M -receptor), probably associated with enterochromaffin cells. Pirenzepine (p. 106) displays a preferential affinity for this receptor subtype. Remarkably, the HCl-secreting parietal cells possess only Ma-receptors. Mi-receptors have also been demonstrated in the brain however, these cannot be reached by pirenzepine because its lipophilicity is too low to permit penetration of the blood-brain barrier. Pirenzepine was formerly used in the treatment of gastric and duodenal ulcers (p. 166). 

Antagonists. Most of the so-called Hi-antihistamines also block other receptors, including M-cholinoceptors and D-receptors. Hi-antihistamines are used for the symptomatic relief of allergies (e.g., bamipine, chlorpheniramine, clemastine, dimethindene, mebhydroline pheniramine) as antiemetics (meclizine, dimenhydrinate, p. 330), as over-the-counter hypnotics (e.g., diphenhydramine, p. 222). Promethazine represents the transition to the neuroleptic phenothiazines (p. 236). Unwanted effects of most Hi-antihistamines are lassitude (impaired driving skills) and atropine-like reactions (e.g., dry mouth, constipation). At the usual therapeutic doses, astemizole, cetrizine, fexofenadine, and loratidine are practically devoid of sedative and anticholinergic effects. Hj-antihistamines (cimetidine, ranitidine, famotidine, nizatidine) inhibit gastric acid secretion, and thus are useful in the treatment of peptic ulcers. 

Fig. 3.25 Structural similarities between agonists at m-cholinoceptors and one selected natural, semisynthetic, as well as synthetic antagonist, respectively in contrast tropisetron is a representative of 5-HT3 antagonists sharing the 3a-acyloxytropane moiety with atropine...

Fig. 3.26 Semisynthetic derivatives of atropine and scopolamine (hyoscine) therapeutictilly used as m-cholinoceptor antagonists highlighted in grey common structural elements shared with the physiological agonist acetylcholine...

Modified and reproduced, with permission, from Wellstein A, Pitschner HF Complex dose-response curves of atropine in man explained by different functions of M-l and M2 cholinoceptors. Naunyn Schmiedebergs Arch Pharmacol 1988 338 19.)... 

The cholinoceptor antagonist pirenzepine preferentially blocks cholinoceptors of the M, type its use in peptic ulcer therapy is now obsolete. 

WAL 2014) is a quinuclidine derivative, a (M,) muscarinic CHOLINOCEPTOR AGONIST. It has been investigated for possible use in cholinergic-replacement therapy for Alzheimer s. 

Postjunctional receptors (N and M) ( in Figure II-2-1) activated by ACh are major targets for both activating drugs (direct-acting cholinomimetics) and cholinoceptor blocking agents. 

He fljiH npoflaacM CKan m fleacaBio-KOHEepcMH MYCAKfl 3t ipoHT.py >- CHOLINOCEPTOR-ACTIVATING CHOLINESTERASE-INHIBITING DRUGS / 61... 

CKaH M fleacaBio-KOHEepcMH MYCARfl 3t ipoHT.py >-CHOLINOCEPTOR BLOCKERS CHOLINESTERASE REGENERATORS / 73... 

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