Synthesis and Pharmacology of Galantamine

ABSTRACT :(-)-Galantamine, an alkaloid isolated from the Caucasian snow-drop (Galanthus woronowii), is a selective, reversible and competitive inhibitor of acetylcholinesterase (AChE), as well as an allosteric modulator of the neural nicotinic receptor for acetylcholine. Galantamine is the most recently approved AChE inhibitor for the symptomatic treatment of Alzheimer’s disease. Because of the limited supplies from natural sources, several total syntheses have been reported to produce this drug. Characterized in the early 1950s in Bulgaria, it saw limited use for paralytic and neuropathic conditions until the cholinergic hypothesis of Alzheimer’s disease opened totally new perspectives for its utility. Although constricted supplies at extremely high prices and a fragmented patent situation made its repurposing challenging, galantamine was globally launched as an Alzheimer’s disease drug in 2000. Galantamine can produce cholinomimetic effects. Overdose effects of cholinergic agonists generally involve the central nervous system, the parasympathetic nervous system, and the neuromuscular junction. alantamine, a tertiary alkaloid, is a reversible, competitive and long-acting inhibitor of cholinesterase activity Keywords – Galantamine, Pharmacological screening,toxicology

2014

Galantamine hydrobromide (GAL) is a reversible acetylcholinesterase inhibitor, with properties to increase the concentration of acetylcholine in several brain structures. The aim of this study is to determine the effect of new galantamine peptide esters: 3,4-dichlorophenyl-alanil-leucil-glycine-galantamine (GAL-LEU) and 3,4-dichlorophenylalanil-valil-glycine-galantamine (GAL-VAL), on locomotor activity in mice and cognitive processes in experimental model of learning and memory in rats. The results showed that per oral administration of GAL-LEU in a dose of 3 mg per kg improved the cognitive processes by increasing the conditional avoidances and learning ability after the 5th day of application and preserved the memory at the 12th day of the study.

Pharmacognosy Communications, 2020

Introduction: Galantamine a traditional herb has also been explored for a number of pharmacological effects. Today, galantamine has been observed for its nootropic effect. Methodology: The objective of this review is to study the evidence of effectiveness and pharmacological effects of galantamine. The preclinical and randomized controlled clinical trials pertaining to studies of galantamine are included. Chemical properties of galantamine and its structure activity relationship pertaining to various biological activities has also been documented. Result and Conclusion: The review revealed protective effects of galantamine on functions and integrity of liver, brain and memory impairment. The various independent studies have demonstrated anti-alzheimer, antioxidant, antidiabetic and neuroprotective effect of galantamine. The present review highlights current information and health-promoting effects of a traditionally known drug galantamine.

Biotechnology & Biotechnological Equipment, 2014

Galantamine hydrobromide (GAL) is a reversible acetylcholinesterase inhibitor, with properties to increase the concentration of acetylcholine in several brain structures. The aim of this study is to determine the effect of new galantamine peptide esters: 3,4-dichlorophenyl-alanil-leucil-glycine-galantamine (GAL-LEU) and 3,4-dichlorophenylalanil-valil-glycine-galantamine (GAL-VAL), on locomotor activity in mice and cognitive processes in experimental model of learning and memory in rats. The results showed that per oral administration of GAL-LEU in a dose of 3 mg per kg improved the cognitive processes by increasing the conditional avoidances and learning ability after the 5th day of application and preserved the memory at the 12th day of the study.

Journal of Pharmacological Sciences, 2011

Several lines of evidence suggest that cholinergic deficits may contribute to the pathophysiology of psychiatric disorders as well as Alzheimer's disease. There is growing clinical evidence that galantamine, currently used for the treatment of Alzheimer's disease, may improve cognitive dysfunction and psychiatric illness in schizophrenia, major depression, bipolar disorder, and alcohol abuse. Since galantamine is a rather weak acetylcholinesterase inhibitor, but has additional allosteric potentiating effects at nicotinic receptors, it affects not only cholinergic transmission but also other neurotransmitter systems such as monoamines, glutamate, and γ-aminobutyric acid (GABA) through its allosteric mechanism. It is likely that these effects may result in more beneficial effects. To understand the underlying mechanism for the clinical effectiveness of galantamine, neuropharmacological studies have been performed in animal models of several psychiatric disorders. These studies suggest that not only the nicotinic receptor-modulating properties but also the muscarinic receptor activation contribute to the antipsychotic effect and improvement of cognitive dysfunction by galantamine. This review summaries the current status on the pharmacology of galantamine, focusing on its effect on neurotransmitter release and pharmacological studies in animal models of psychiatric disorders.

Bioorganic & Medicinal Chemistry, 2015

The inhibitors of acetylcholinesterase are the main therapy against Alzheimer's disease. Among them, galantamine is the best tolerated and the most prescribed drug. In the present study, 41 galantamine derivatives with known acetylcholinesterase inhibitory activities expressed as IC 50 were selected from the literature and docked into a recombinant human acetylcholinesterase by GOLD. A linear relationship between GoldScores and pIC 50 values was found and used to design and predict novel galantamine derivatives with indole moiety in the side chain. The four best predicted compounds were synthesized and tested for inhibitory activity. All of them were between 11 and 95 times more active than galantamine. The novel galantamine derivatives with indole moiety have dual site binding to the enzyme-the galantamine moiety binds to the catalytic anionic site and the indole moiety binds to peripheral anionic site. Additionally, the indole moiety of one of the novel inhibitors binds in a region, close to the peripheral anionic site of the enzyme, where the X-loop of amyloid beta peptide adheres to acetylcholinesterase. This compound emerges as a promising lead compound for multi-target anti-Alzheimer therapy not only because of the strong inhibitory activity, but also because it is able to block the amyloid beta deposition on acetylcholinesterase.

Turkish Journal of Pharmaceutical Sciences

Recent Patents on CNS Drug Discovery, 2012

Galanthamine is a selective, reversible competitive acetylcholinesterase inhibitor that has been recently approved for the symptomatic treatment of Alzheimer's disease. Galanthamine is a natural product belonging to the Amaryllidaceae family of alkaloids. The pharmacological history of galanthamine shows that the bioactive compound was discovered accidentally in the early 1950s, and the plant extracts were initially used to treat nerve pain and poliomyelitis. In addition, galanthamine had since been tested for use in anesthesiology, from facial nerve paralysis to schizophrenia. Galanthamine is a long-acting, selective, reversible and competitive AChE inhibitor that has recently been tested in AD patients and found to be readily absorbed, to be a performance enhancer on memory tests in some patients, and to be well tolerated, although some cholinergic side effects were observed. A number of total synthetic approaches have been reported, and a method for the industrial scale-up preparation of galanthamine is now being developed and patented. A variety of galanthamine derivatives have also been synthesized aiming to develop an agent free from cholinergic adverse effects. Galanthamine is a natural product that complements other synthetic drugs for the management of AD. In this account we will review the recent patent literature showing the most important advance on the chemistry of galanthamine.

2018

Galantamine (GAL) is a well-known acetylcholinesterase (AChE) inhibitor, and it is widely used for treatment of Alzheimer's disease. GAL fits well in the catalytic site of AChE, but it is too short to block the peripheral anionic site (PAS) of the enzyme, where the amyloid beta (Aβ) peptide binds and initiates the Aβ aggregation. Here, we describe a docking-based technique for designing of GAL derivatives with dualsite binding fragments-one blocking the catalytic site and another blocking the PAS. The highly scored compounds are synthesized and tested. Protocols for docking, design, synthesis, and AChE inhibitory test are given.