Muscarinic specificity

Initial attempts to treat AD using direct cholinergic agonists were limited by low efficacy and side-effect issues (140—142). Thus trials using RS-86 (25), oxotremorine [70-22-4] (26), arecoline [63-75-2] (27), and pilocarpine [92-32-7] (28) to treat AD were equivocal (Eig. 5). However, the identification of multiple subtypes of muscarinic receptors has stimulated a search for subtype specific muscarinic agonists which may limit side effects while increasing efficacy. 

Alkaloids are heterocyclic basic compounds and widespread in plants. Many of them have specific targets in organisms. For example, the alkaloids atropine and scopolamine of Belladonna are specific antagonists at muscarinic receptors. 

Older tricyclic antidepressants are set in italics. The specificity of action of tricyclic antidepressants (in particular of amitritpyline, imipmmine, doxepine, noitriptyline, maprotiline) is limited because at therapeutic levels ihese drugs also block receptors (H t-histamine, a,-adrenergic, muscarinic). 

The rate of non-lgE-mediated immediate hypersensitivity reactions usually varies between 20 and 50% [1-7, 9], They are assumed to result from direct non-specific mast cell and basophil activation, which causes direct histamine release [19], Histamine release is predominantly found with the use of the benzylisoquinoUnes d-tubocurarine, atracurium and mivacurium, and the aminosteroid rapacuronium. Severe bronchospasm related to rapacuronium administration has been reported in children and adults. It might be related to the higher affinity of rapacuronium for M2 versus M3 muscarinic receptors [20]. Rapacuronium has been withdrawn from the market in the USA. 

In view of the preponderance of muscarinic receptors in the CNS and the conceived need to augment the muscarinic actions of ACh in the treatment of Alzheimer s disease, much attention has been given recently to the synthesis of agonists that penetrate the blood-brain barrier, especially those that act specifically on M] receptors. 

Few drugs, apart from nicotine itself, act specifically on nicotine receptors. One is methylcarbachol, which lacks the muscarinic effects of carbachol and another is dimethylphenylpiperazinium (DMPP), which appears to have some selectivity for the neuronal nicotinic receptor. Neither of them can cross the blood-brain barrier. 

Hersch, SM, Guten Kunst, CA, Rees, HD, Heilman, CT and Levey, AJ (1994) Distribution of M1-M4 muscarinic receptor proteins in the rat striatum. Light and electron microscopic immunochemistry using subtype-specific antibodies. J. Neurosci. 141 3351-3363. 

Levey, A, Kitt, CA, Simmonds, WF, Price, DL and Brann, MR (1991) Identification and localisation of muscarinic acetylcholine receptor proteins in brain with subtype specific antibodies. J. Neurosci. 11 3218-3226. 

The excitatory muscarinic receptors on GABA/ENK neurons are Mi but those on the GABA/SP neurons are probably M4 and inhibitory. A study of more specific Mi and M4 antagonists in PD therapy may be appropriate. 

No overall reduction in cholinergic muscarinic receptors was found but recent studies with relatively specific ligands show a loss of presynaptic M2 receptors, in keeping with the loss of terminals, but no reduction in postsynaptic Mi receptors. Some acetylcholinesterase is found in plaques. 

Datta, S., Quattrochi, J. J. Hobson, J. A. (1993). Effect of specific muscarinic M2 receptor antagonist on carbachol induced long-term REM sleep. Sleep 16, 8-14. 

Velazquez-Moctezuma, J., Gillin, J. C. Shiromani, P. J. (1989). Effect of specific Ml, M2 muscarinic receptor agonists on REM sleep generation. Brain Res. 503, 128-31. 

Anticholinergic Drugs that block acetylcholine receptors, although the term is used specifically for antagonists at muscarinic acetylcholine receptors (anti-muscarinics), like atropine and scopolamine. 

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