Serotonin Receptor Binding Characteristics of Geissoschizine Methyl Ether, an Indole Alkaloid in Uncaria Hook

Abstract

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 symp-toms 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 sub-types in the brains using our own data and previous findings.Methods: 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 me-tabolized 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 cor-tex.Conclusion: These results suggest that GM is a pharmacologically important alkaloid that regulates vari-ous 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.

Characteristic Chromatogram: A Method of Discriminate and Quantitative Analysis for Quality Evaluation of Uncaria Stem with Hooks

“…HTI was also shown to decrease blood pressure in anesthetized rats [17]. Moreover, GSM improved the behavioral and psychological symptoms of dementia through various serotonin receptors [18]. Thus, these nine common alkaloids were selected as markers of the quality of URM, and the SSDMC method was validated using the same chromatographic parameters.…”

Dissecting the Metabolic Phenotype of the Antihypertensive Effects of Five Uncaria Species on Spontaneously Hypertensive Rats

“…As a complex, multifactorial disease, hypertension is closely associated with genetic, environmental, and metabolic factors, being the most vital risk factor for cardiovascular and chronic kidney diseases (Perry et al, 1995). Indole alkaloids are recognized as the active pharmacological components of UHs (Chen et al, 2010; Zhou and Zhou, 2012; Yasushi et al, 2018). Our previous research has also shown that the methanol extract of five UHs had very different chromatographic fingerprints using LC-MS (Pan et al, 2015; Pan et al, 2017; Hou et al, 2018; Pan et al, 2018).…”

Basic Study of Drug-Drug Interaction between Memantine and the Traditional Japanese Kampo Medicine Yokukansan

“…MEM is a single chemical compound, whereas YKS is composed of seven crude drugs, and at least 25 ingredients that have been identified by three-dimensional liquid chromatographic analysis with ultraviolet detection [14]. Among these ingredients, GM [21] and GA [16] are predicted to be active ingredients responsible for the ameliorative effect of YKS on BPSD-like phenotypes, and ILQG [20] has an antagonistic action against NMDA receptors similar to that of MEM. Therefore, we performed pharmacokinetic studies to evaluate the DDI between MEM and the three YKS-derived ingredients.…”

“…Glycyrrhetinic acid (GA), a main metabolite of glycyrrhizic acid derived from Glycyrrhiza, was reported to normalize the reduced expression of glutamate transporters in cultured astrocytes subjected to thiamine deficiency [16]. Furthermore, geissoschizine methyl ether (GM), found in Uncaria hooks, has a partial agonistic action on serotonin 1A receptors, and is a candidate for the psychopharmacological effect of YKS [21], as well as GA.…”