Galanthamine hydrobromide
[CAS 1953-04-4]

Identification

• Classification: API >> Nervous system medication >> Cholinergic
• Name: Galanthamine hydrobromide
• Synonyms: (1S,12S,14R)-9-methoxy-4-methyl-11-oxa-4-azatetracyclo[8.6.1.01,12.06,17]heptadeca-6(17),7,9,15-tetraen-14-ol;hydrobromide
• Molecular Formula: C₁₇H₂₁NO₃.HBr;C₁₇H₂₂BrNO₃
• Molecular Weight: 368.27
• CAS Registry Number: 1953-04-4
• EC Number: 217-780-5
• SMILES: CN1CC[C@@]23C=C[C@@H](C[C@@H]2OC4=C(C=CC(=C34)C1)OC)O.Br

Properties

• Solubility: Soluble 50 mM in water, DMSO: <7mg/mL (Expl.)

Safety Data

• Hazard Symbols: GHS06;GHS07 Danger
• Risk Statements: H301-H315-H317-H331
• Safety Statements: P261-P264-P270-P271-P272-P280-P301+P316-P302+P352-P304+P340-P316-P321-P330-P332+P317-P333+P317-P362+P364-P403+P233-P405-P501

Hazard Classification

Hazard	Class	Category Code	Hazard Statement
Acute toxicity	Acute Tox.	3	H301
Acute toxicity	Acute Tox.	3	H331
Skin sensitization	Skin Sens.	1	H317
Skin irritation	Skin Irrit.	2	H315
Acute hazardous to the aquatic environment	Aquatic Acute	1	H400
Chronic hazardous to the aquatic environment	Aquatic Chronic	1	H410
Eye irritation	Eye Irrit.	2	H319
Specific target organ toxicity - repeated exposure	STOT RE	2	H373
Acute toxicity	Acute Tox.	1	H300
Acute toxicity	Acute Tox.	3	H311

• Transport Information: UN 2811

Discovery and Applications

Galanthamine hydrobromide is the hydrobromide salt form of galanthamine, a naturally occurring alkaloid originally isolated from plants in the Amaryllidaceae family, including species such as Galanthus (snowdrops) and related genera. The salt form is used to improve stability, handling, and formulation properties compared with the free base.

Galanthamine itself is a tertiary amine alkaloid with a complex polycyclic structure consisting of a benzazepine-like aromatic system fused to a bicyclic framework containing multiple stereocenters. This rigid, three-dimensional architecture is a defining feature of the molecule and contributes to its specific binding interactions with biological targets.

The molecule contains a tertiary amine nitrogen that is protonated in the presence of hydrobromic acid to form galanthamine hydrobromide. In this salt form, the nitrogen carries a positive charge, balanced by a bromide anion. Salt formation increases aqueous solubility and improves pharmaceutical formulation characteristics by enhancing dissolution and stability.

Structurally, galanthamine includes a methoxy-substituted aromatic ring and several oxygen-containing functional groups, including ether and alcohol functionalities. These groups contribute to hydrogen bonding and polarity, while the aromatic system contributes hydrophobic character and π-electron interactions. The balance between polar and nonpolar regions supports interaction with biological macromolecules.

Galanthamine is best known for its interaction with acetylcholinesterase (AChE), an enzyme responsible for the breakdown of the neurotransmitter acetylcholine. It functions as a reversible inhibitor of AChE, thereby increasing acetylcholine levels in synaptic clefts. This mechanism is associated with modulation of cholinergic signaling in the nervous system. In addition to enzyme inhibition, galanthamine also interacts with nicotinic acetylcholine receptors as an allosteric potentiating ligand, although the extent and physiological relevance of this interaction depend on concentration and biological context.

The hydrobromide salt does not significantly alter the intrinsic pharmacological activity of galanthamine but primarily affects its physicochemical properties. Salt formation is a common strategy in medicinal chemistry to optimize solubility, bioavailability, and manufacturability without modifying the active molecular framework.

From a stereochemical perspective, galanthamine contains multiple chiral centers, and its biological activity is highly dependent on its specific stereochemical configuration. The naturally occurring form exhibits the pharmacological properties described above, while stereoisomers may differ in potency or activity.

In terms of physicochemical behavior, galanthamine hydrobromide is expected to be significantly more water-soluble than the neutral base due to its ionic character. The protonated amine interacts strongly with water molecules, while the bromide ion contributes to ionic dissociation in solution. Despite this, the molecule retains substantial lipophilicity due to its fused ring system, enabling it to cross biological membranes.

Historically, galanthamine was first isolated in the mid-20th century from plant sources and later synthesized chemically for broader study and therapeutic use. Its discovery contributed to the development of acetylcholinesterase inhibitors as a class of compounds used in neuropharmacology research.

Overall, galanthamine hydrobromide is a protonated alkaloid salt derived from a complex polycyclic natural product. Its significance lies in its well-characterized interaction with acetylcholinesterase and its use as a stabilized, water-soluble form of galanthamine for pharmaceutical and research applications.

References

2023. Multimodal action of KRP203 on phosphoinositide kinases in vitro and in cells. Biochemical and Biophysical Research Communications.
DOI: 10.1016/j.bbrc.2023.08.050