Background: Geissoschizine methyl ether (GM) is one of the indole alkaloids in Uncaria
hook, and an active ingredient of yokukansan (YKS) that improves behavioral and psychological symptoms
of dementia (BPSD) in patients with several types of dementia. The pharmacological action of GM
has been related to various serotonin (5-HT) receptor subtypes.
Objective: The aim of this article is to review the binding characteristics of GM to the 5-HT receptor
subtypes in the brains using our own data and previous findings.
Method: Competitive receptor-binding and agonist/antagonist activity assays for several 5-HT receptor
subtypes were performed. Moreover, the articles describing pharmacokinetics and brain distribution of
GM were searched in PubMed.
Results: GM bound the following 5-HT receptor subtypes: 5-HT1A, 5-HT1B, 5-HT2A, 5-HT2B, 5-HT2C, 5-
HT4, 5-HT5A, 5-HT6, and 5-HT7. Among these receptors, GM had partial agonistic activity for 5-HT1A
receptors and antagonistic activity for 5-HT2A, 5-HT2B, 5-HT2C, and 5-HT7 receptors. Also, GM was
metabolized by various CYP isoforms, mainly CYP3A4. Parent/unchanged GM was detected in both the
blood and brain of rats after oral administration of YKS. In the brains, GM was presumed to bind to 5-
HT1A, 5-HT2A, 5-HT2B, 5-HT2C, and 5-HT7 receptors on neuron-like large cells mainly in the frontal cortex.
Conclusion: These results suggest that GM is a pharmacologically important alkaloid that regulates
various serotonergic activities or functions by binding to multiple 5-HT receptor subtypes. Thus, this
review provides recent 5-HT receptor-related evidence that GM is partly responsible for pharmacological
effects of YKS.