Galantamine (trade name Razadyne®, Reminyl®) (2, 3) or galanthamine is an drug used for the treatment of mild to moderate Alzheimer’s disease (1, 2, 3, 4, 5, 6). It is usually used as its hydrobromide. Galantamine in its pure form is a white powder. It is an alkaloid that has been obtained from the bulbs and flowers of Caucasian snowdrop (Voronov’snowdrop), Galanthus woronowii (Amaryllidaceae) and related species. This active ingredient was discovered accidentally by a Bulgarian pharmacologist in 1950s. (6, 7).

Pharmacology

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(1)

Galantamine binds to the base of the active site, gorge of the enzyme acetyl-cholinesterase, which spans the acyl binding site and the choline binding site. Galantamine forms two hydrogen bonds to the enzyme acetyl-cholinesterase. The first hydrogen bond is formed between the hydroxyl group of the inhibitor and the Glu-199 Oε1. The second hydrogen bond is formed between the hydroxyl group of Ser-200 bifurcated with His-440 Nε2 and the oxygen of the O-methyl group of Galantamine. It is possible to have another hydrogen bond between the N-methyl group of Galantamine and Asp-72 Oδ2, this is a non-classical hydrogen bond as the methyl group has to carry some of the positive charge of the amine. The active site of acetyl-cholinesterase has a polyethylene glycol (PEG) molecule; the terminal hydroxyl group of PEG interacts with the tertiary amine of Galantamine. (7). All the other interactions between Galantamine and acetyl-cholinesterase is non-polar. The natural substance acetylcholine that binds to acetyl-cholinesterase has a quaternary amine and it interacts with Trp-84 and Phe-330 of the enzyme acetyl-cholinesterase, but Galantamine’s protonated tertiary amine does not interact with these two amino acids of the enzyme. The next methylene in the tetrahydroazepine ring has three interacts with the indole ring of the enzyme. Cyclohexane ring of Galantamine interacts with Trp-84. There is a double bond in the cyclohexane ring that stacks against the pi system of the indole ring of the enzyme. Saturation of this double bond gives rise to lycoramine which can greatly reduce the affinity of Galantamine. In the acyl binding pocket Galantamine’s O-methoxy group interacts with Phe-288 and Phe290 of the enzyme. There are no direct charge to charge interactions between Galantamine and Acetyl-cholinesterase enzyme residues. Galantamine has a bent hinge shape that helps the tight binding of Galantamine to the enzyme. Because of the rigidity of the Galantamine molecule there is a low entropic cost when binding to the enzyme with high affinity. (7)

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