Muscarinic acetylcholine receptor antagonists

D.R. Hwang, C.S. Dence, Z.A. McKinnon, C.J. Mathias, M.J. Welch, Positron labeled muscarinic acetylcholine-receptor antagonist—2-[F-18]Fluorodexetimide and 4-[F-18]fluorodexetimide—Synthesis and biodistribution, Nucl. Med. Biol. 18 (1991) 247-252. 

Riekkinen M, Sirvio J, Toivanen T, et al Combined treatment with a 5-HTj, receptor agonist and a muscarinic acetylcholine receptor antagonist disrupts water maze navigation behaviour. Psychopharmacology 122 137-146, 1995... 

Hyoscyamine (atropine) muscarinic acetylcholine receptor (antagonistic)... 

Total Synthesis of Cyclostellettamine C, a Bispyridinium Macrocyclic Alkaloid Having Muscarinic Acetylcholine Receptor Antagonistic Activity. Anan, H. Seki, N Noshiro, O Honda, K Yasumuro, K. Ozaka, T. and Fusetani, N. Tetrahedron 1996, 52, 10849. 

Renaissance women enlarged the pupils of their eyes to appear more attractive using atropine-containing extracts of A. belladonna. Atropine, the racemic form of hyoscyamine, is a muscarinic acetylcholine receptor antagonist used to dilate the pupil during... 

Anan, H., Seki, N., Noshiro, O., Honda, K., Yasumuro, K., Ozasa, T.. and Fusetani, N. (1996) Total synthesis of cydosteUettamine C, a bispyridinium macrocydic alkaloid having muscarinic acetylcholine receptor antagonistic activity. Tetrahedron, 52,10849-10860. 

Antagonists of muscarinic acetylcholine receptors had widely been used since 1860 for the treatment of Parkinson s disease, prior to the discovery of l-DOPA. They block receptors that mediate the response to striatal cholinergic interneurons. The antiparkinsonian effects of drugs like benzatropine, trihexyphenidyl and biper-iden are moderate the resting tremor may sometimes respond in a favorable manner. The adverse effects, e.g., constipation, urinary retention, and mental confusion, may be troublesome, especially in the elderly. 

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

Reaper, C.M., Fanelli, F., Buckingham, S. D Millar, N.S. and Sattelle, D.B. (1998) Antagonist profile and molecular dynamic simulation of a Drosophila melanogaster muscarinic acetylcholine receptor. Receptors Channels, 5,... 

Nicotine affects the nervous system, interacting with the nicotinic acetylcholine receptors, and the tight binding is partially accounted for by the structural similarity between acetylcholine and nicotine. Curare-like antagonists also block nicotinic acetylcholine receptors (see Box 6.7). There are other acetylcholine receptors, termed muscarinic, that are triggered by the alkaloid muscarine. The tropane alkaloid hyoscyamine (see Box 10.9) binds to muscarinic acetylcholine receptors. 

The TCAs have affinity for both receptors and transporters of monoamine transmitters and behave as antagonists in both respects. Thus, the neuronal reuptake of norepinephrine (p. 82) and serotonin (p. 116) is inhibited, with a resultant increase in activity. Muscarinic acetylcholine receptors, a-adrenocep-tors, and certain 5-HT and hista-mine(Hi) receptors are blocked. Interference with the dopamine system is relatively minor. 

Certain plants of the family Solanaceae, such as Atropa belladonna L., Hyoscyamus niger L., and Datura stramonium L., have been used medicinally for centuries in Europe because they contain tropane-type alkaloids.For example, atropine (1) [a racemic mixture of (+)- and (—)-hyoscyamine (2)] and (-)-hyoscyamine are competitive antagonists at the muscarinic acetylcholine receptor site, leading to antispasmodic and antiallergic effects. Scopolamine [(—)-hyoscine)] (3) is used in a transdermal patch for the prevention of motion sickness. Since these tropane alkaloids penetrate the blood-brain barrier, they also have psychoactive effects. ... 

The mechanisms of action of phencyclidine and ketamine are complex (Gorelick Balster, 1995). The drugs are non-competitive antagonists at NMDA receptors, and also bind to associated phencyclidine/sigma opioid receptors. They also have agonist actions at dopamine receptors, complex interactions with both nicotinic and muscarinic acetylcholine receptors and poorly understood interactions with noradrenergic and serotonergic systems. These multiple actions may combine to produce delirium and psychotic reactions. 

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... 

Mechanism of Action A urinary antispasmodic t hat act s as a direct antagonist at muscarinic acetylcholine receptors in cholinergically innervated organs. Reduces tonus (elastictension) of smooth muscle in the bladder and slows parasympathetic contractions. Therapeutic Effect Decreases urinary bladder contractions, increases residual urine volume, and decreases detrusor muscle pressure. 

Miyamoto et al. have also demonstrated in the dry skin and itch mouse model (water + acetone ether treated) that the scratching response can be inhibited by the use of atropine, a nonspecific muscarinic acetylcholine receptor (mAChR) antagonist, and 4-diphenyl-acetoxy-N-methyl-piperidine (4-DAMP), an M3 mAChR antagonist.32 They further showed that Mi and M2 mAChR antagonist were not able to inhibit the scratch response. This report suggests the role of acetylcholine, and the M3 specific receptor as a potential player in dry-skin-associated pruritus. In addition, skin biopsies in human subjects with atopic dermatitis were found to have increased levels of acetylcholine compared with normal controls, which suggests that abnormal concentrations of neurotransmitters may also be involved in itch secondary to xeroderma.33... 

An important advance in PET related chemistry was achieved by Welch and Wolf and their coworkers,388,389 who were able to use the K18F/2.2.2-kryptofix combination for aromatic nucleophilic substitution of activated aromatic rings, which could serve as starting materials for more complex products. Welch and coworkers started with nitrobenzalde-hyde, which was converted to [18F]fluorobenzaldehyde making eventually [18F]fluorodexetimide 62 (equation 224) which acts as a muscarinic acetylcholine receptor (mAchR) antagonist. It was used for PET brain studies since acetylcholine receptors are... 

Muscarinic Acetylcholine receptor (mACh-R) — antagonists Alkaloid Atropine (= d,l-Hyoscamine Tropine ( )-tropate ester) (racemate of hyoscamine)... 

Worsening parkinsonism was observed in two patients after treatment with olanzapine 5 mg/day (114). In contrast, coarse tremors induced by fluphenazine or haloper-idol disappeared in three patients within days of the start of treatment with olanzapine (10 mg/day), without discontinuation or reduction in the dosage of fluphenazine or haloperidol (115). Olanzapine is active at muscarinic cholinergic receptors, which may account for the observed suppression of neuroleptic drug-induced tremor however, two of the three patients had been taking ben-zatropine, an antagonist at muscarinic acetylcholine receptors, with little tremor relief, suggesting that olanzapine could suppress tremor by means of an action other than muscarinic blockade. 

Honda, H., Tomizawa, M., and Casida, J.E., Insect muscarinic acetylcholine receptor Pharmacological and toxicological profiles of antagonists and agonists, j. Agric. Food Chem., 55, 2276, 2007. 

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