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New Acetylcholinesterase Inhibitors

Dateline: 04/06/98

By Alan Bruzel

The neurotransmitter acetylcholine is the chemical responsible for many nerve to nerve and nerve to muscle signaling events. For example, nerve A signals nerve B by sending it a pulse of acetylcholine. After the acetylcholine evokes a response, it must immediately be broken down by the enzyme acetylcholinesterase to prevent further nervous stimulation. Prescription and non-prescription substances that prevent this breakdown, and thus permit continued stimulation, modify acetylcholinesterase either irreversibly (organophosphorous compounds, see Nerve Gases, Part I), or reversibly (carbamates and oximes, see Nerve Gases, Part II). Most therapeutic regimens produce reversible inhibition of acetylcholinesterase. The temporary enzyme inactivation causes a consequent temporary rise in acetylcholine that can be beneficial. For example, the carbamates physostigmine and pyridostigmine transiently boost acetylcholine levels to ameliorate myasthenia gravis and Alzheimer's disease symptoms. The reduced number of acetylcholine receptors in myasthenia gravis patients gain access to a larger pool of acetylcholine. Alzheimer's disease patients, whose acetylcholine levels are abnormally low, experience improved cognition. These time-proven drugs form a covalent, but reversible, modification of acetylcholinesterase's active site. Newer anticholinesterases do not chemically modify the enzyme at all, but reversibly bind to its aromatic amino acids through pi electron interactions. This can be appreciated by understanding acetylcholinesterase's molecular structure.

The existence of an enzyme that removes excess acetylcholine was postulated in 1914, shown experimentally in 1926, and isolated in crude form in 1932. Today, acetylcholinesterase's protein sequence and three-dimensional structure are known, as well as its gene's DNA sequence and location on human chromosome 7. X-ray crystallography reveals the enzyme's catalytic region with its three closely spaced areas: the peripheral site, the gorge, and the active site. The peripheral site is 14 ångstroms (Å; 1 Å = 1 X 10^-10 meters) from the rim of the gorge: a narrow cleft lined with fourteen aromatic amino acids. The bottom of the gorge, 20 Å below the surface of the enzyme, houses the active site. Here, the enzyme's serine residue reacts with acetylcholine, forming an acetylated serine intermediate. Hydrolysis of this intermediate, which takes place in milliseconds, regenerates the active enzyme. The peripheral site, the gorge, and the active site are all potential targets for noxious or medicinal chemicals.

All the compounds discussed below, except metrifonate, are reversible inhibitors of acetylcholinesterase. Metrifonate, like other organophosphorous compounds, irreversibly inactivates the enzyme.

BW284c51 (1,5-bis(4-Allyldimethylammoniumphenyl)-pentan-3-one dibromide)

When bound to acetylcholinesterase, the bis quaternary inhibitor BW284c51 spans from the enzyme's peripheral site to its active site.

Decamethonium (N,N,N,N',N',N'-Hexamethyl-1,10-decanediammonium dibromide)

Decamethonium is another bis quaternary compound that spans from peripheral site to active site.

Donepezil ((±)-2,3-Dihydro-5,6-dimethoxy-2- 1 [[1-(phenylmethyl)-4-piperidinyl]methyl]-1H-inden-1-one)

The US Food and Drug Administration (FDA) approved donepezil (marketed by Eisai and Pfizer as Aricept) for use in Alzheimer's disease. It is less toxic to the liver than tacrine (below), but its clinical efficacy has been questioned.

Edrophonium (Ethyl(m-hydroxyphenyl)dimethylammonium chloride)

Edrophonium binds to acetylcholinesterase's active site. It is a muscle relaxant administered by injection, with effects lasting about ten minutes.

Gallamine (2,2',2"-[1,2,3 Benzene-triyltris(oxy)]- tris[N,N,N-triethylethanaminium] triiodide)

Gallamine binds to acetylcholinesterase's peripheral site. It is also an injectable muscle relaxant, and its effects last about thirty minutes.

Metrifonate (Trichlorofon) (O,O-Dimethyl- 1-hydroxy- 2,2,2-trichloroethyl- phosphonate)	Dichlorvos (O,O-Dimethyl- O-2,2-dichlorovinyl phosphate)

Metrifonate, known to the pesticide industry as trichlorofon, is under study as a long-acting drug for Alzheimer's disease. It has previously been used medically in the treatment of schistosomiasis. In the body, it breaks down to dichlorvos, another organophosphorous pesticide, which permanently inactivates acetylcholinesterase by covalent modification of the active site. Metrifonate presently awaits FDA approval as an anticholinesterase.

Propidium (3,8-Diamino-5-(3-(diethylmethylamino)propyl)- 6-phenyl phenanthridinium diiodide)

Like gallamine, propidium binds to acetylcholinesterase's peripheral site. It is primarily a laboratory reagent used for fluorescent staining of DNA and RNA.

Tacrine (1,2,3,4-Tetrahydro-9-acridinamine)

Approved by the FDA for treatment of Alzheimer's disease, tacrine (marketed by Warner-Lambert as Cognex) binds to acetylcholinesterase's active site.

Two tacrine molecules with a 7-carbon spacer

This tacrine analog, still undergoing evaluation, is about one thousand times more potent than tacrine in inhibiting acetylcholinesterase activity.

Many more acetylcholinesterase inhibitors are under study. These include:
1.) Tetracyclic compounds related to the tricyclic tacrine (see J Med Chem, 40, 3516, 1997),
2.) TAK-147 (3-[1-(Phenylmethyl)-4-piperidinyl]-1-(2,3,4,5-tetrahydro-1H-
1-benzazepin- 8-yl)-1-propanone fumarate),
3.) the fasciculins: 61 amino acid peptides from the venom of the black mamba (Dendroaspis polylepis) and green mamba (D. angusticeps),
4.) antisense oligonucleotides that prevent cellular synthesis of acetylcholinesterase, and
5.) electromagnetic radiation, reported to inhibit acetylcholinesterase activity at certain radio frequencies.

These therapies may not only alleviate disease symptoms in defined patient populations, but may well pave the way to memory enhancement for everyone else.

Recommended Web resources for additional information:

Alzheimer's disease treatments
Drugs, vitamins, and other modalities for Alzheimer's disease patients.

ESTHER database
Copious information on acetylcholinesterase inhibitors.

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