Muscarinic activity

Haj-Dahmane S, Andrade R 1996 Muscarinic activation of a voltage-dependent cation nonselective current in rat association cortex. J Neurosci 16 3848-3861 Hardie RC, Minke B 1993 Novel Ca2+ channels underlying transduction in Drosophila photoreceptors implications for phosphoinositide-mediated Ca2+ mobilization. Trends Neurosci 16 371-376... 

Wolf-Pflugmann M, Lambrecht G, Wess J, Mutschler E. (1989). Synthesis and muscarinic activity of a series of tertiary and quaternary N-substituted guvacine esters structurally related to arecoline and arecaidine propargyl ester. Arzneimittelforschung. 39(5) 539-44. 

Bieger D. (1984). Muscarinic activation of rhombencephalic neurones controlling oesophageal peristalsis in the rat. Neuropharmacology. 23(12A) 1451-64. 

As indicated in Chapter 6, muscarinic receptor subtypes have been characterized by binding studies and cloned. Several cellular events occur when muscarinic receptors are activated, one or more of which might serve as second messengers for muscarinic activation. All muscarinic receptors appear to be of the G protein-coupled type (see Chapter 2 and Table 7-1). Muscarinic agonist binding activates the inositol trisphosphate (IP3), diacylglycerol (DAG) cascade. Some evidence... 

Pathophysiology can influence muscarinic activity in other ways as well. Circulating autoantibodies against the second extracellular loop of cardiac M2 muscarinic receptors have been detected in some patients with idiopathic dilated cardiomyopathy and those afflicted with Chagas1 disease caused by the protozoan Trypanosoma cruzi. These antibodies exert parasympathomimetic actions on the heart that are prevented by atropine. In animals immunized with a peptide from the second extracellular loop of the M2 receptor, the antibody is an allosteric modulator of the receptor. Although their role in the pathology of heart failure is unknown, these antibodies should provide clues to the molecular basis of receptor activation because their site of action differs from the orthosteric site where acetylcholine binds (see Chapter 2). 

Remarkable is the fact that 73a and 73b, showing the greatest difference in sub-lethal activity and toxicity, exhibit the same action under invitro conditions. Both compounds were found to be antagonists of the muscarinic activity of acetylcholine and carbachol71. The dose-response curves of acetylcholine antagonized by 73a and 73b were identical within experimental error. 

A ring system that is able to restrict conformational flexibility while minimizing additional bulk is cyclopropane. As a strained system, its angles differ from the standard 60° and 180° possibilities with cyclohexane. The (+)-trans cyclopropane analogue (9.26) does show muscarinic activity comparable to acetylcholine (Figure 9.13). The dihedral angle between the ester and ammonium group is approximately 145°. The (—)-trans enantiomer and both... 

Several 1,3-dioxolanes have been shown to have muscarinic activity. Of these, (124 X = O) is a particularly selective agonist at muscarinic receptors, the cis being 5-10 times more active than the trans. The corresponding oxathiolane (124 X = S) also had high activity. A compound of close structural similarity, dioxonium (125), is a muscle relaxant in man. 

Bethanechol [be THAN e kole] is structurally related to acetylcholine the acetate is replaced by carbamate and the choline is methylated (see Figure 4.5). Hence, it is not hydrolyzed by acetylcholinesterase, although it is inactivated through hydrolysis by other esterases. It has little or no nicotinic actions but does have strong muscarinic activity. Its major actions are on the smooth musculature of the bladder and gastrointestinal tract. It has a duration of action of about 1 hour. 

Pilocarpine exhibits muscarinic activity and is primarily used in ophthalmology. 

Haloperidol Little adrenergic or muscarinic activity. Available as slow release depot form ... 

Several organs are the target for the anticholinergic (anti-muscarinic) activity of the tricyclic antidepressants. They constitute the most common and troublesome adverse effects of the tricyclic antidepressants, but the peripheral anticholinergic actions can also be put to therapeutic use in conditions such as irritable bowel syndrome, premature ejaculation, and nocturnal enuresis. 

Shortening or lengthening the chain of atoms that separates the e.ster group from the onium moiety reduces mu.s-carinic activity. An a substitution on the choline moiety decreases both nicotinic and muscarinic activity, but muscarinic activity is decreased to a greater extent. Nicotinic activity is decreased to a greater degree by substitution on the... 

The "five atom rule," first suggested by Alles and Knoefel (38) and stated more formally by Ing (39), proposesthat, for maximum muscarinic activity, there should be attached to the quaternary nitrogen atom, in addition to three methyl groups, a fourth group with a chain of five atoms, as illustrated for acetylcholine C-C-O-C-C-N. This empirical observation has been found to be valid for a large number of molecules, regardless of the precise nature of the five atoms involved. 

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