Muscarinic acetylcholine receptor agonists

C]RS 86,281, a muscarinic acetylcholine receptor agonist, has been synthesized from nor-RS 86 (R = H, R = Et) and [ C]CH3l in 5-7% yield with specific activity 150-170 mCi mmol . The biodistribution of 281 in rats has been studied and a 1.1% uptake of injected dose of 281 per organ at 5 min has been observed, which decreased to 0.62 at 30 rain. 

Jakubic, J., and El-Fakahany, E. E. (1997). Positive coopera -tivity of acetylcholine and other agonists with allosteric ligands on muscarinic acetylcholine receptors. Mot. Pharmacol. 52 172-177. 

Positive cooperativity of acetylcholine and other agonists with allosteric ligands on muscarinic acetylcholine receptors. Mol. Pharmacol. 52 172—179. 

Anatoxin-a is the most potent and most stereospecific nicotinic acetylcholine receptor agonist thus far identified. It is also highly selective for nicotinic receptors over muscarinic receptors. The molecular parameters which influence the binding affinity, channel activation, channel blockade, and receptor desensitization are being studied. Modifications of the carbonyl and amine moieties can reduce or nearly eliminate the receptor agonist potency of the compounds and also determine the channel blocking characteristics. 

J. S. Gutkind, E. A. Novotny, M. R. Brann, and K. C. Robbins. Muscarinic acetylcholine receptor subtypes as agonist-dependent oncogenes. Proc. Natl Acad. Sci. U.S.A. 88 4703-4707,1991. 

Acetylcholine All four alkaloids derived from areca (arecoline, arecaidine, guvacoline, and guvacine) act as full agonists at muscarinic acetylcholine receptors (Wolf-Pflugmann et al. 1989). Peripherally administered arecoline (10 mg/kg) subtly reduces cortical and subcortical acetylcholine levels (Molinengo et al. 1986). 

Areca (Areca catechu) is a tall palm tree that yields a nut, commonly chewed in Asia for its stimulant effects. It is discussed at greater length in chapter 4, but is mentioned here briefly for its cognitive effects. Areca s psychoactive constituents (arecoline, arecaidine, guvacoline, and guvacine) are agonists at muscarinic acetylcholine receptors. They also directly inhibit reuptake of GABA. 

Acetyichoiine Muscarine is an agonist at muscarinic acetylcholine receptors, for which the receptor was named. It is not certain what role this plays in the psychoactive effects of amanita. 

Muscarinic acetylcholine receptors a class of acetylcholine receptors for which muscarine is the iconic agonist. 

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. 

Many different receptor types are coupled to G proteins, including receptors for norepinephrine and epinephrine (a- and p-adrenoceptors), 5-hydroxytrypta-mine (serotonin or 5-HT receptors), and muscarinic acetylcholine receptors. Figure 2.1 presents the structure of one of these, the uz-adrenoceptor from the human kidney. All members of this family of G protein-coupled receptors are characterized by having seven membrane-enclosed domains plus extracellular and intracellular loops. The specific binding sites for agonists occur at the extracellular surface, while the interaction with G proteins occurs with the intracellular portions of the receptor. The general term for any chain of events initiated by receptor activation is signal transduction. 

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... 

An example of a receptor coupled to an ion channel is the muscarinic acetylcholine receptor, which brings about opening of a K channel on agonist binding. There is evidence that the Py subunits of the corresponding heterotrimeric G-protein are involved in opening of the ion channel. 

Yamakawa, T., Ando, M. Koito, S., Ohwaki, K., Kimura, T., Saeki, T., Miyaji, M., Iwahori, Y., Fujikawa, T., Otake, N., Noguchi, K. (Banyu Pharmaceutical Co.) Preparation of substituted imidazolidinone derivatives as agonists of muscarinic acetylcholine receptor M4, W00127104 (2001). 

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. 

Feron O, Smith TW, Michel T, Kelly RA. Dynamic targeting of the agonist-stimulated m2 muscarinic acetylcholine receptor to caveolae in cardiac myocytes. J Biol Chem 1997 272 17,744-17,748. 

---