Muscarine derivative

Interest in the synthesis of desether muscarine derivatives (6) has developed owing to their activity and specificity, which parallel those of the muscarines. In order to overcome deficiencies in overall yield of a previous photochemical synthesis, a new stereoselective route has been devised (Scheme 1). The readily available cyclo-pentene amide (3) was epoxidized to give (4), which upon treatment with lithium dimethylcuprate provided the amido-alcohol (5). Metal hydride reduction followed... 

An organometallic route to muscarine derivatives has been developed (Scheme 1). Reduction of the aa -dibromo-ketone (1) with Fe2(CO)9 in the presence of DMF provided the furanone (2) in good yield. Acetylation of (2) afforded the corresponding enol acetate, which upon Mannich reaction with dimethylamine and formaldehyde gave the furan derivative (3). Deacetylation followed by dissolving-metal reduction and quaternization with methyl iodide gave two isomeric 4-methyl-muscarine salts (4). These compounds showed physiological properties characteristic of the muscarine alkaloids. 

Reduction of a furanose ditosylate. Joullid et al. have reported a facile synthesis of a muscarine derivative (4) from the furanose 1, obtainable from D-glucose. Reduction of 1 with lithium aluminum hydride gives a mixture of 2 and 3, considered to be formed via an epoxide (a). Indeed reduction of a, prepared by a standard method, gives the same mixture of 2 and 3. The former product was converted into D-epiallomuscarine (4). 

The reduction of a,a -dibromo ketones in the presence of jV.A -dialkylated carboxamides generally leads to the formation of 3(2//)-furanones of type CLXXIX. A. A -Dimethylformamide, yv,A -dimethylacetamide, A. A -dimethyl-benzamide, and A -methylpyrrolidone can be used as carboxamide. A muscarine derivative (CLXXXI) has been prepared from CLXXX in several steps (Noyori et al., 1973e). 

Muscarine derivatives were the target of another synthesis, which starts off with a simple aldol condensation between (65) and (66). A novel method of dihydrofuran formation was achieved by reaction of the dienone derivative (67) with ethylene glycol and p-toluenesulphonic acid to give (68). ° The success of the reaction, which would appear to contravene Baldwin s Rules, was attributed to the formation of the delocalized carbonium ion (69). 

The antimuscarinic drug atropine, and its derivative ipratropiumbromide, can also be used for antiarrhyth-mic treatment. Muscarinic receptors (M2 subtype) are mainly present in supraventricular tissue and in the AV node. They inhibit adenylylcyclase via G proteins and thereby reduce intracellular cAMP. On the other hand, activation of the M2 receptor leads to opening of hyperpolarizing Ik.acii and inhibits the pacemaker current If probably via the (3y-subunit of the Gi protein associated with this receptor. The results are hyperpolarization and slower spontaneous depolarization. Muscarinic receptor antagonists like atropine lead to increased heart rate and accelerated atrioventricular conduction. There are no or only slight effects on the ventricular electrophysiology. 

Muscarinic M3 Receptor. A pharmacophore model was derived from known M3 receptor antagonists, using the program DISCO, and 3D searching was performed by Unity 3D in the Astra Charnwood in-house compound repository and the databases of several commercial suppliers. The 172 compounds that fitted the pharmacophore were screened for their M3-antagonistic potency. Several compounds with micromolar and even submicromolar activities resulted, for example, compound 13 (A50 M3 antagonism 0.2pM pA2 = 6.67 Fig. 16.2) [85],... 

Some agonists, such as methacholine, carbachol and bethanecol are structurally very similar to ACh (Fig. 6.6). They are all more resistant to attack by cholinesterase than ACh and so longer acting, especially the non-acetylated carbamyl derivatives carbachol and bethanecol. Carbachol retains both nicotinic and muscarinic effects but the presence of a methyl (CH3) group on the p carbon of choline, as in methacholine and bethanecol, restricts activity to muscarinic receptors. Being charged lipophobic compounds they do not enter the CNS but produce powerful peripheral parasympathetic effects which are occasionally used clinically, i.e. to stimulate the gut or bladder. 

Because the SSRIs are derived from different chemical groups, their receptor interactions vary from compound to compound but, apart from paroxetine, none of them shows any appreciable binding to muscarinic receptors, a prime objective of their development. However, compared with other SSRIs, fluoxetine binds with moderately high affinity to human 5-HT2A (.K) 280 nM) and 5-HT2C receptors (Aij 55 nM) sertraline is a relatively potent ligand for ai-adrenoceptors, 2-adrenoceptors and Dj receptors and citalopram shows appreciable binding to 5-HTia, oc]-adrenoceptors and Hi receptors (Table 20.6 Stanford 1996). The extent to which any of these receptor interactions affects the efficacy of these compounds is not known. 

As shown in table 6, we have compared the affinities of a series of methylenedioxy derivatives with those of the parent compounds (amphetamine and methamphetamine) at some of the recognition sites in brain at which MDMA exhibited the highest affinities. These comparative studies indicate that addition of the methylenedioxy subshtuent in the 3,4 position inereases their affinity at serotonin uptake, 5-HT2 serotonin, and M-1 muscarinic receptors, while the unsubstituted parent compounds appear to be more potent at Ct2-iadrenergic receptors. 

Gharagozloo P, Lazareno S, Popham A, Birdsall N. Allosteric interactions of quaternary strychnine and brucine derivatives with muscarinic acetylcholine receptors. J Med Chem 1999 42 438-445. 

The reaction of 5-[2-(iV,./V-dimethylamino)ethyl]-l,2,4-oxadiazole with methyl iodide forms the quaternary ammonium salt 170 (Scheme 22), which undergoes elimination in the presence of base (diisopropylethylamine (DIEA), TEA, l,8-diazabicyclo[4.3.0]undec-7-ene, etc.) to form an intermediate 5-vinyl-l,2,4-oxadiazole 171, which undergoes in situ Michael addition with nucleophiles to furnish the Michael adducts 172. As an example, also shown in Scheme 22, 3-hydroxy-pyrrolidine allows the synthesis of compound 172a in 97% yield. Mesylation followed by deprotonation of the 1,2,4-oxadiazole methylene at C-5 enables Sn2 displacement of the mesylate to give the 5-azabicycloheptyl derivative 173, which is a potent muscarinic agonist <1996JOC3228>. 

The Stille coupling of tetraethyltin and chloropyrazine 15 led to ethylpyrazine 16, which was an important intermediate for preparing quinuclidinylpyrazine derivatives as muscarinic agonists [13]. In this particular case, the reductive elimination took place faster than (3-hydride elimination. 

Ueber Muscarin, 15. Mitteilung. Reduktion Normuscaron mit Borwasserstoff und bi-cyclische Derivate der Muscarinreihe, by E. Hardegger and N. Haider, Helv. Chim. Acta, 50 (1967) 1275-1283. 

The presence of a dichloromethylene group at the anomeric center of 82 facilitates proton abstraction at C-3 by a strong base (77), aifording the 4-deoxyglycos-3-ulose derivative 83. Reduction of the dichloromethylene group by Raney nickel gave a 1-C-methyl derivative with high stereospecificity, which opens the way to a series of 2,5-anhydro-l-deoxyalditols. Compound 83 was the key intermediate for the synthesis (78) of tosyl L-(+)-epi-muscarine (84a) and tosyl L-(+)muscarine (84b). 

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). 

The psychoactive constituents of fly agaric are amino acid derivatives (Eugster et al. 1965 Schultes and Flofman 1980, 1992). These include ibotenic acid, muscimol, muscazone, muscarine, and (R)-4-hydroxy-... 

Muscarine is a tetrahydrofuran derivative with the structure shown in Figure 3.7a. Because of the three chirality centers present in the molecule, muscarine exists in eight isomers, of which only one, L-(- -)-muscarine, is active. The remaining isomers also have been detected in toxic fungi, but because of their low biological activity and low concentration they do not contribute to toxicity. 

Things turn out to be a bit more complex than I have suggested thus far. Acetylcholine is also known to cause contraction of skeletal muscle and to slow the rate of heartbeat. However, muscarine does neither of these things nor are these actions of acetylcholine blocked by atropine. Another plant-derived molecule, nicotine from tobacco, proved to be an acetylchohne agonist at skeletal muscle and heart. 

Another well-known hallucinogen is psilocybin from the mushroom genus Psilocyhe Fig. 11.13). Muscarine is an isoxazole derivative (Fig. 11.13). Table 11.3 lists some of the hallucinogens in plants. 

The muscarinic ACh receptors (of which there are at least five subtypes) are metabotropic. Their name is derived from the alkaloid muscarine, which is found in the fly agaric mushroom (Amanita muscaria), for example. Like ACh, muscarine is bound at the receptor, but in contrast to ACh (see C), it is not broken down and therefore causes permanent stimulation of muscle. 

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