Muscarinic cholinergic receptor ligands

This potent [18F]-labelled muscarinic cholinergic receptor ligand 142182,183 has been synthesized184 by reductive amination of [2-18F]- and [4-18F]fluorobenzaldehyde with norben-zyldexetimide185a and sodium cyanoborohydride in a one-pot reaction (equation 92). Specific activities were 500-4000 mCi mmol-1 (142) (for the 2-fluoro compound) and 2400-8000 mCi mmol-1 (for the 4-fluoro compound). 

Fanelli, F., Menziani, M.C., Carotti, A. and De Benedetti, P.G. (1993). Theoretical Quantitative Structure-Activity Analysis of Quinuclidine-Based Muscarinic Cholinergic Receptor Ligands. J.Mol.Struct.(Theochem), 102, 63-71. 

Both [2- F] and [4- F]fluorobenzaldehydes are key intermediates in the synthesis of N-[ F]fluorobenzylamines via reductive aminations. This methodo o-gy has been successfully appHed to the preparation of a potential ace y -cholinesterase inhibitor [143] and of fluoro analogues of dexetimide, potent ligand of muscarinic cholinergic receptor [144] (Scheme 23). 

S ATP -I- muscarinic cholinergic receptor <3> (<3> from chick heart [7-9] <3> in vitro as good as -adrenergic receptor, phosphorylation depends on the presence of a muscarinic agonist ligand, not merely receptor occupancy, the agonist induces a conformational change, which allows phosphorylation, phosphorylation sites 70% Ser- and 30% Thr-residues, incorporation of 3-4 mol phosphate/mol receptor [7]) (Reversibility <3> [7-9]) [7-9]... 

After binding of ligands, many neurotransmitter receptors (e.g., the dopamine, adrenergic, GABAb, metabotropic glutamate, and muscarinic cholinergic receptors)... 

Drubbisch V, Drubbisch V, Lameh J, Philip M, et al., Mapping the ligand binding pocket of the human muscarinic cholinergic receptor Hml contribution of tyrosine-82. Pharm Res 1992 9 1644-1647. 

Acetylcholine (ACh) is an example of an endogenous neurotransmitter that binds to more than one receptor type, the nicotinic acetylcholine receptor (nAChR) which preferentially binds nicotine and the muscarinic receptor which binds muscarine, a mushroom alkaloid. The latter is a G protein-coupled receptor while the nACh receptor is an excitatory ligand-gated ion channel that transports Na-i- ions. Nicotinic cholinergic receptors are found in the CNS, autonomic ganglia, and at the neuromuscular junction of skeletal muscles. They are a possible target for anaesthetics. 

Acetylcholine receptors. There are numerous receptors for ACh (Fig. 12—10), of which the major subtypes are nicotinic and muscarinic subtypes of cholinergic receptors. Classically, muscarinic receptors are simulated by the mushroom alkaloid muscarine and nicotinic receptors by the tobacco alkaloid nicotine. Nictotinic receptors are all ligand-gated, rapid-onset, and excitatory ion channels, which are blocked by curare. Muscarinic receptors, by contrast, are G protein—linked, can be excitatory or inhib-... 

Greig NH, Reale M, Tata AM (2013) New pharmacological approaches to the cholinergic system an overview on muscarinic receptor ligands and cholinesterase inhibitors. Recent Pat CNS Drug Discov 8 123-141... 

The muscarinic cholinergic system has quite a different mode of operation in that the receptor is connected to the final action by a chain of events. Thus its response is slower than the nicotinic, where the receptor and ion channel are closely connected. Five distinct muscarinic receptors have been identified in mammals, based on anatomical location, genetic analysis, function, and amino acid sequence. All of them have seven transmembrane domains [166, 167, 168, 169]. The N- terminal domain outside the cell binds acetylcholine or other ligands at a site that includes an aspartate residue, while the C-terminal domain inside the cell is coupled to a so-called G-protein , which is initially bound to guanosine diphosphate (GDP), but exchanges it for guanosine triphosphate (GTP) when activated by its transmitter. The activated G-protein then activates phospholipase C, which hydrolyzes phosphoinositides to release 1,4,5-inositol triphosphate [170]. The final action depends on which type of cell is involved so that in some types ion channels are opened just as with the nicotinic receptor, but in other cases other processes are affected, for example the release of dopamine [171]. Since there are these differences... 

No overall reduction in cholinergic muscarinic receptors was found but recent studies with relatively specific ligands show a loss of presynaptic M2 receptors, in keeping with the loss of terminals, but no reduction in postsynaptic Mi receptors. Some acetylcholinesterase is found in plaques. 

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