Acetylcholine chemistry

Medicinal chemistry has many examples of the development of successful therapeutics based on an exploration of endogenous compounds. The treatment of diabetes mellitus, for example, is based upon the administration of insulin, the hormone that is functionally deficient in this disease. The current treatment of Parkinson s disease is based upon the observation that the symptoms of Parkinson s disease arise from a deficiency of dopamine, an endogenous molecule within the human brain. Since dopamine cannot be given as a drug since it fails to cross the blood-brain barrier and enter the brain, its biosynthetic precursor, L-DOPA, has been successfully developed as an anti-Parkinson s drug. Analogously, the symptoms of Alzheimer s disease arise from a relative deficiency of acetylcholine within the brain. Current therapies for Alzheimer s-type dementia are based upon the administration of cholinesterase... 

There are two main families of ligand-gated ion channel proteins that act as ionotropic receptors. One family includes the nicotinic acetylcholine receptor, the GABA-A receptor, the glycine receptor, and a class of serotonin receptor. The other family comprises various types of ionotropic glutamate receptors. Since these various ligand gated ion channels are activated by neurotransmitters, the medicinal chemistry of these proteins is presented in detail in chapter 4. 

The medicinal chemistry of Alzheimers is complicated by the fact that the etiology of this disease is still far from clear. Evidence points to an association with decreased levels of acetyl choline in the brain. Many of the drugs that have been introduced to date for treating this disease thus comprise agents intended to raise the deficient levels of that neurotransmitter by inhibiting the loss of existing acetylcholine due to the action of cholinesterase. A compound based on an indene that, perhaps surprisingly, inhibits that enzyme has been proposed for the treatment of Alzheimer s. Aldol condensation of piperidine aldehyde (4-2) with the indanone (4-1) from cyclization of 3,4-dimethoxycinnamic acid leads to the olefin (4-3). Catalytic reduction removes the double bond to afford donepezil (4-4) [3]. 

The competition for nAChR binding by acetylcholine and nicotine illustrates the key role of selectivity in binding in supramolecular chemistry. Because nAChR is not fully selective, it is also able to bind the interfering nicotine. The fact that nicotine, like acetylcholine, possesses a quaternary ammonium moiety that is implicated in its binding mechanism highlights the dependence of biological processes on ostensibly weak supramolecular interactions. 

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... 

The rapid development of carborane chemistry is mainly due to their practical applications. For instance, the potential utility of carborane polymers as gaskets, O-rings, and electrical connector inserts has been reported. Their functionality for solvent extraction of radionuchdes as well as the potential medicinal value of the isoelectronic and isostructural boron analogues of biologically important molecules has been the subject of many review articles. For example, a number of boron compounds have been found to possess anti-inflammatory and antiarthritic activity in animal model studies. Boron compounds have also been implicated in studies designed to probe the importance of the so-called anionic subsite of acetylcholine esterase and Ach receptors. But, by far the most interesting practical apphcations of carboranes are in areas of boron neutron capture therapy (BNCT) and supramolecular assembly. 

Acetylcholinesterase. A pronounced decrease in the level of the neurotransmitter acetylcholine is one of the most pronounced changes in brain chemistry observed in the sufferers of Alzheimer s disease (139). Several drugs that are approved for the treatment of the dementia thought to result from this neurotransmitter deficit act by inhibiting acetylcholinesterase. These include (63) (tacrine, or... 

R.J. Lind, D.T. Greenhow, J. Blythe, J. Goodchild, E. Hirst, S.J. Dunbar and F.G.P. Earley, Cyanotropanes Novel Chemistry Interacting at the Insect Nicotinic Acetylcholine Receptor in BCPC Conference - Pests Diseases, British Crop Protection Council, 2002, Vol. 1, pp. 145-152. 

McDonald, I.A., Cosford, N., Vernier, J.-M., 1995. Nicotinic acetylcholine receptors molecular biology, chemistry and pharmacology. Annu. Rep. Med. Chem. 30, 41-50. 

DISCOVERY OF ABT-594 AND RELATED NEURONAL NICOTINIC ACETYLCHOLINE RECEPTOR MODULATORS AS ANALGESIC AGENTS MEDICINAL CHEMISTRY AND BIOLOGY... 

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