Tetrahydropalmatine (THP) is an isoquinoline alkaloid found in several different plant species, mainly in the genus Corydalis (Yan Hu Suo), but also in other plants such as Stephania rotunda. These plants have traditional uses in Chinese herbal medicine. The pharmaceutical industry has synthetically produced the more potent enantiomer Levo-tetrahydropalmatine (Levo-THP; technically l-THP, often written L-THP), which has been marketed worldwide under different brand names as an alternative to anxiolytic and sedative drugs of the benzodiazepine group and analgesics such as opiates. It is also sold as a dietary supplement. In 1940, a Vietnamese scientist Sang Dinh Bui extracted an alkaloid from the root of Stephania rotunda with the yield of 1.2–1.5% and he named this compound rotundin. From 1950 to 1952, two Indian scientists studied and extracted from Stephania glabra another alkaloid named hyndanrine. In 1965, the structure of rotundine and hyndarin was proved to be the same as tetrahydropalmatine.
Effects Tetrahydropalmatine has been demonstrated to possess analgesic effects and may be beneficial in the treatment of heart disease and liver damage. It is a blocker of voltage-activated L-type calcium channel active potassium channels. It is a potent muscle relaxant. It is widely used in China as a sedative. It has also shown potential in the treatment of drug addiction to both cocaine and opiates, and preliminary human studies have shown promising results. In animal models, anti-addiction effects can manifest at sub-sedative doses.
Adverse effects In November 2013, the Chinese National Medical Products Administration issued an order asking for all medications containing l-THP to have their package inserts revised, prohibiting use in pregnant women and those with extrapyramidal disorders, requiring warnings about liver impairement and operation of machinery, and highlighting risks of drowsiness and extrapyramidal symptoms with overuse or when combined with other CNS depressants. Long-term is not advised. The same order lists the following OTC medications as containing l-THP:
Mechanism of action The pharmacological profile of l-THP includes antagonism of dopamine D1, and D2 receptors as well as actions at dopamine D3, alpha adrenergic and serotonin receptors. The Ki values for l-THP at D1 and D2 dopamine receptors are approximately 124 nM (D1) and 388 nM (D2). In addition to the antagonism of postsynaptic dopamine receptors, the blockade of presynaptic autoreceptors by l-THP results in increased dopamine release, and it has been suggested that lower affinity of l-THP for D2 receptors may confer some degree of autoreceptor selectivity. Along with dopamine receptors, l-THP has been reported to interact with a number of other receptor types, including alpha-1 adrenergic receptors, at which it functions as an antagonist, and GABAA receptors, through positive allosteric modulation. Additionally, l-THP displays significant binding to 5-HT1A and alpha-2 adrenergic receptors. In the case of 5-HT1A receptors, l-THP binds with a Ki of approximately 340 nM.
Animal experiments have shown that the sedative effect of THP results from blocking dopaminergic neurons in the brain. Dopamine is an important neurotransmitter in the central nervous system where it occurs in several important signaling systems that regulate muscular activity and attention, as well as feelings of joy, enthusiasm, and creativity. THP causes no feelings of euphoria, and has been seen as an alternative to addictive drugs for people suffering from anxiety and pain, and as a possibility for relief for people not helped by existing drugs. Induction of ΔfosB by antipsychotics in the prefrontal cortex — which may extend to the D2 receptor antagonism of l-THP — has been associated with negative behavioural outcomes. Chronic blockade of dopaminergic receptors has been associated with weight gain, apathy, metabolic syndrome, extrapyramidal symptoms, tardive dyskinesia which can be permanent, neuroleptic malignant syndrome, reduced cognitive function, reduced brain matter volume and increased ventricular or fluid volume.
Biosynthesis The biosynthesis of tetrahydropalmatine starts with tyrosine and proceeds via (S)-reticuline in a pathway leading to benzylisoquinoline alkaloids. The final step is a methylation reaction by the enzyme tetrahydrocolumbamine 2-O-methyltransferase using the cofactor, S-adenosyl methionine (SAM). This transfers a methyl group, giving S-adenosyl-L-homocysteine (SAH) as a by-product.
Tetrahydropalmatine can be metabolised by the enzyme tetrahydroberberine oxidase, which oxidises it to palmatine:
Safety L-THP has a pharmacokinetic profile that is favorable for clinical use. L-THP has a long-standing record of safe use in China for a number of indications under the trade-name Rotundine. Concerns about liver toxicity and sedation associated with the use of some l-THP containing herbal preparations in the US are likely due to poor quality and improper use of these unregulated products.
Research The University of Maryland has completed a phase I study for THP in people with a history of cocaine use. Their phase II study for cocaine use disorder was withdrawn due to a lack of funding. l-THP does not improve psychiatric symptoms when added on top of antipsychotics in schizophrenia.
See also
References
External links Introduction to Rotundine ZINC entry
