Cholinergic agonists muscarinic

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. 

The oral cholinergic agonists pilocarpine and cevimeline are used for patients with combined dry eye and dry mouth (e.g., Sjogren s syndrome) or severe dry eye. By binding to muscarinic receptors, the cholinergic agonists may increase tear production. Excessive sweating is a common side effect with pilocarpine and may limit its use (Table 60-10). 

Raffaele KC, Berardi A, Asthana S, Morris P, Haxby JV, Soncrant TT. (1991). Effects of long-term continuous infusion of the muscarinic cholinergic agonist arecoline on verbal memory in dementia of the Alzheimer type. Psychopharmacol Bull. 27(3) 315-19. 

Mecfianism of Action A cholinergic agonist that binds to muscarinic receptors of effector cells, thereby increasing secretion of exocrine glands, such as salivary glands. Therapeutic Effect Relieves dry mouth. 

Acetylcholine acts at two different types of cholinergic receptors [see (1) and (2) in Fig. 2.5]. Muscarinic receptors bind ACh as well as other agonists (muscarine, pilocarpine, bethanechol) and antagonists (atropine, scopolamine). There are at least five different types of muscarinic receptors (M1-M5). All have slow response times. They are coupled to G proteins and a variety of second messenger systems. When activated, the final effect can be to open or close channels for K, Ca ", or CL (Bonner, 1989). Nicotinic receptors are less abundant than the muscarinic type in the CNS. They bind ACh as well as agonists such as nicotine or an-... 

Increased stimulation of the AChR can be achieved in two ways (1) by binding of the directly acting cholinergic agonists to the AChR, triggering nicotinic or muscarinic... 

Other cholinergic agonists have no therapeutic use. Muscarine (4.3) is an alkaloid of the mushroom Anumita muscaria muscarone (4.9) is its semisynthetic analog. Pilocarpine (2.2) is found in the leaves of a shrub and can be used to increase salivation or sweating. Arecoline (4.10) is also an alkaloid, and occurs in the betel nut that is used as a mild euphoriant in India and Southeast Asia. Finally, oxotremorine (4.11) is a synthetic experimental agent that produces tremors and is helpful in the study of antiparkinsonian drugs. 

Berkowitz, A., Sutton, L., Janowsky, D.S., Gillin, J.C. Pilocarpine, an orally active muscarinic cholinergic agonist, induces REM sleep and reduces delta sleep in normal volunteers. Psychiatry Res. 33. 112—119. 1990. 

Xie G et al Cholinergic agonist-induced pepsinogen secretion from murine gastric chief cells is mediated by Mi and M3 muscarinic receptors. Am J Physiol 2005 289 G521. 

L(+)-Muscarine, a cholinergic agonist from the mushroom Amanita muscaria... 

Muscarinic receptor A primary class of cholinergic receptors that are named according to their affinity for the muscarine toxin. Certain cholinergic agonists... 

Acetylcholine (9.12) binds both types of cholinergic receptors muscarinic and nicotinic (Figure 9.9). The names of these receptor types were based on muscarine (9.13) and nicotine (9.14), selective agonists for each receptor. A muscarinic response is characterized by nausea, salivation, and tearing. Nicotinic responses are noted by an acceleration of the heart rate. Acetylcholine s ability to elicit a response from both subtypes of receptors may imply that different conformations of acetylcholine may be responsible for binding to each receptor. 

Laplante F, Nakagawasai O, Srivastava LK, Quirion R. 2005. Alterations in behavioral responses to cholinergic agonists in post-pubertal rats with neonatal ventral hippocampal lesions Relationship to changes in muscarinic receptor levels. Neuropsychopharmacology 30 1076-1087. 

An alkaloid of natural plant origin, pilocarpine is a direct-acting cholinergic agonist with a dominant action at both peripheral and central muscarinic sites. The cholinomimetic action of pilocarpine on smooth muscle muscarinic receptors generally results in contraction.The response of intraocular smooth muscle to pilocarpine is pupillary constriction, spasm of accommodation, and reduction of lOP. 

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