Central nervous system muscarinic receptor antagonists

Atropine, an alkaloid from Atropa belladonna, is the classical parasympatholytic compound. It competes with acetylcholine for the binding at the muscarinic receptor. Its affinity towards nicotinic receptors is very low, so that it does not interfere with the ganglionic transmission or the neuromotor transmission, at least in therapeutic dosages. However, in the central nervous system muscarinic receptor do play an important role and while atropine can penetrate the blood-brain barrier it exerts pronounced central effects. Atropine, like all other antagonists of the muscarinic acetylcholine receptor inhibit the stimulatory influence of the parasympathetic branch of the autonomous nervous system. All excretory glands (tear, sweat, salivary, gasto-intestinal, bronchi) are... 

Tertiary-amine muscarinic receptor antagonists gain access to the central nervous system and are therefore the anticholinergic drugs used to treat parkinsonism and the extrapyramidal side effects of antipsychotic drugs. Specific agents used primarily for these conditions include benztropine mesylate (Cogentin) and trihexyphenidyl hydrochloride (Artane, others). 

Waelbroeck M, Gillard M, Robberecht P, Christophe J (1987) Muscarinic receptor heterogeneity in rat central nervous system. I. Binding of four selective antagonist to three muscarinic receptor subclasses a comparison with M2 cardiac muscarinic receptors of the C type. Mol. Pharmacol, 52, 91-99. 

Because muscarinic receptors are involved in a variety of physiological processes in peripheral organs as well as in the central nervous system, numerous studies have been aimed at understanding the relationship between structure and activity of muscarinic agonists and antagonists. Better understanding of these relationships may eventually lead to the development of new drugs for specific diseases, such as Parkinson s disease and Alzheimer s disease. 

S)-Hyoscyamine and (6)-scopolamine are esters of the amino alcohols tropine and scopine with ( S)-tropic acid, which is derived from phenylalanine (Fig. 3). The two alkaloids occur exclusively in the Solanaceae family. They act as antagonists of muscarinic acetylcholine receptors (parasympatholytics) and lead to an increase in pulse rate, relaxation of smooth muscles, e.g., in the gastrointestine and the bronchial tract, reduction of salivary, bronchial, gastric, and sweat gland secretion. While hyoscyamine is a central stimulant, scopolamine depresses the central nervous system. 

The parasympathetic division is the dominant portion of the pulmonary autonomic nervous system in all mammals. Airway smooth muscle is richly supplied with muscarinic receptors and stimulation of M3 receptors results in smooth muscle contraction and bronchoconstriction. Cholinergic stimulation is the primary mechanism of bronchospasm in horses with recurrent airway obstruction (Robinson et al 1996). Parasympathetic innervation can be demonstrated throughout the tracheobronchial tree of the horse but smooth muscle contraction evoked by stimulation of cholinergic nerves is more pronounced in the trachea than in the smaller bronchi. It is expected that parasympathetic blockade with a muscarinic antagonist will have the greatest effect in large, central airways. 

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