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


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 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.


CONCLUSIONS
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.
Tsumura Kampo Research Laboratories, Kampo Research & Development Division, Tsumura & Co., 3586 Yoshiwara, Ami-machi, Inashiki-gun, Ibaraki 300-1192, Japan.
Yasushi
Y
Ikarashi
Tsumura Kampo Research Laboratories, Kampo Research & Development Division, Tsumura & Co., 3586 Yoshiwara, Ami-machi, Inashiki-gun, Ibaraki 300-1192, Japan.
Kyoji
K
Sekiguchi
Tsumura Kampo Research Laboratories, Kampo Research & Development Division, Tsumura & Co., 3586 Yoshiwara, Ami-machi, Inashiki-gun, Ibaraki 300-1192, Japan.
Kazushige
K
Mizoguchi
D000818:Animals; D001667:Binding, Competitive; D001921:Brain / Q000378:metabolism; D004365:Drugs, Chinese Herbal / Q000737:chemistry; D006801:Humans; D026121:Indole Alkaloids / Q000737:chemistry / Q000302:isolation & purification / Q000378:metabolism*; D011485:Protein Binding; D051381:Rats; D011985:Receptors, Serotonin / Q000737:chemistry / Q000378:metabolism*; D032070:Uncaria / Q000737:chemistry*
D004365:Drugs, Chinese Herbal; D026121:Indole Alkaloids; D011985:Receptors, Serotonin; C524644:Yi-Gan San; C110832:geissoschizine methylether
5-HT receptor; BPSD; Geissoschizine methyl ether; dementia.; pharmacokinetics; pharmacological aspect; yokukansan