(-)-Huperzine A
[CAS# 102518-79-6]

Identification

• Classification: API >> Nervous system medication >> Cholinergic
• Name: (-)-Huperzine A
• Synonyms: (-)-Selagine
• Molecular Formula: C₁₅H₁₈N₂O
• Molecular Weight: 242.32
• CAS Registry Number: 102518-79-6
• EC Number: 600-320-6
• SMILES: C/C=C/1[C@@H]2CC3=C([C@]1(CC(=C2)C)N)C=CC(=O)N3

Properties

• Density: 1.2±0.1 g/cm³ Calc.^*
• Boiling point: 505.0±50.0 °C 760 mmHg (Calc.)^*
• Flash point: 259.2±30.1 °C (Calc.)^*
• Index of refraction: 1.626 (Calc.)^*

^* Calculated using Advanced Chemistry Development (ACD/Labs) Software.

Safety Data

• Hazard Symbols: GHS06;GHS07 Danger
• Risk Statements: H300-H310-H315-H319-H330-H335
• Safety Statements: P260-P261-P262-P264-P264+P265-P270-P271-P280-P284-P301+P316-P302+P352-P304+P340-P305+P351+P338-P316-P319-P320-P321-P330-P332+P317-P337+P317-P361+P364-P362+P364-P403+P233-P405-P501

Hazard Classification

Hazard	Class	Category Code	Hazard Statement
Acute toxicity	Acute Tox.	2	H300
Skin irritation	Skin Irrit.	2	H315
Eye irritation	Eye Irrit.	2	H319
Acute toxicity	Acute Tox.	2	H310
Specific target organ toxicity - single exposure	STOT SE	3	H335
Acute toxicity	Acute Tox.	1	H330
Acute toxicity	Acute Tox.	2	H330
Chronic hazardous to the aquatic environment	Aquatic Chronic	2	H411
Acute toxicity	Acute Tox.	1	H310

Discovery and Applications

(-)-Huperzine A is a Lycopodium alkaloid originally isolated from the clubmoss Huperzia serrata. After its isolation, its structures, along with those of the related alkaloid huperzine B, were elucidated and shown to possess marked anticholinesterase activity. The compound is a potent, reversible inhibitor of acetylcholinesterase, the enzyme responsible for hydrolyzing acetylcholine in cholinergic synapses. Its molecular formula is C₁₅H₁₈N₂O, and it is optically active; the naturally occurring enantiomer is the one commonly studied in biology and medicine. Early chemical characterization revealed a polycyclic framework characteristic of Lycopodium alkaloids and helped to anchor subsequent synthetic and pharmacological investigations.

A major milestone in understanding the compound’s mechanism came from structural biology. An X-ray crystallographic study of the enzyme–inhibitor complex demonstrated how (-)-huperzine A binds in the active site gorge of acetylcholinesterase, forming key interactions that explain both its high affinity and its selectivity. The resolved complex clarified the orientation of the bicyclic system, the positioning of the amide carbonyl toward the catalytic machinery, and how the ligand spans subsites within the gorge. These insights guided medicinal chemistry around huperzine scaffolds and aided interpretation of structure–activity relationships across a variety of designed analogs and bivalent derivatives.

Following its discovery, (-)-huperzine A became an important pharmacological probe for cholinergic neuroscience. In biochemical assays, it has been widely used as a reference acetylcholinesterase inhibitor to benchmark potency and kinetics of new inhibitors. In neurophysiology and behavioral pharmacology, it has been employed to transiently elevate synaptic acetylcholine and study cholinergic contributions to learning, memory, and attention. Because it is reversible and crosses the blood–brain barrier, it has served as a tool compound in preclinical models exploring cholinergic modulation.

Clinically, (-)-huperzine A has been evaluated for cognitive disorders, most notably Alzheimer’s disease. A multicenter, randomized, double-blind, placebo-controlled phase II study in individuals with mild to moderate Alzheimer’s disease assessed safety, tolerability, and efficacy over a 16-week treatment period. Although cholinesterase inhibition is an established symptomatic strategy for dementia, the trial’s outcomes highlighted both the safety profile and the limits of efficacy under the tested conditions. Across the broader clinical literature, the compound has been further examined in various dosing regimens and formulations, and it has been used as an active comparator or adjunct in exploratory studies, reflecting ongoing interest in cholinergic augmentation.

Outside formal trials, (-)-huperzine A has influenced drug design campaigns aimed at cholinesterase targets and has inspired analogs engineered to adjust brain penetration, duration, and multi-target properties. The structural template has also been integrated into hybrid molecules intended to interact with additional pathways implicated in neurodegenerative disease. In parallel, total syntheses and process routes have been reported, facilitating access for research and enabling controlled quality useful for pharmacological studies.

As a natural product with a well-defined target, (-)-huperzine A occupies a distinct place at the interface of natural products chemistry and neurotherapeutics. Its discovery established Huperzia species as a source of bioactive alkaloids; its structural elucidation and crystallographic characterization provided a concrete mechanistic foundation; and its applications range from a biochemical standard for enzyme inhibition to a clinically tested cholinergic agent. Together, these developments illustrate how a plant alkaloid progressed from isolation and structural assignment to a widely used molecular tool and an investigational therapy, while also seeding ongoing medicinal chemistry around its scaffold.

References

Liu JS, Zhu YL, Yu CM, Zhou YZ, Han YY, Wu FW, Qi BF (1986) The structures of huperzine A and B, two new alkaloids exhibiting marked anticholinesterase activity. Canadian Journal of Chemistry 64(4) 837–839 DOI: 10.1139/v86-137

Raves ML, Harel M, Pang YP, Silman I, Kozikowski AP, Sussman JL (1997) Structure of acetylcholinesterase complexed with the nootropic alkaloid, (-)-huperzine A. Nature Structural Biology 4(1) 57–63 DOI: 10.1038/nsb0197-57

Rafii MS, Walsh S, Little JT, Behan K, Reynolds B, Ward C, Jin S, Thomas R, Aisen PS (2011) A phase II trial of huperzine A in mild to moderate Alzheimer disease. Neurology 76(16) 1389–1394 DOI: 10.1212/WNL.0b013e318216eb7b