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An Investigation of the Differential Effects of Ursane Triterpenoids from Centella asiatica , and Their Semisynthetic Analogues, on GABA A Receptors
Author(s) -
Hamid Kaiser,
Ng Irene,
Tallapragada Vikram J.,
Váradi Linda,
Hibbs David E.,
Hanrahan Jane,
Groundwater Paul W.
Publication year - 2016
Publication title -
chemical biology and drug design
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.59
H-Index - 77
eISSN - 1747-0285
pISSN - 1747-0277
DOI - 10.1111/cbdd.12766
Subject(s) - centella , receptor , chemistry , gabaa receptor , amide , stereochemistry , carboxylic acid , xenopus , biochemistry , biology , botany , gene
The ursane triterpenoids, asiatic acid 1 and madecassic acid 2 , are the major pharmacological constituents of Centella asiatica , commonly known as Gotu Kola, which is used traditionally for the treatment of anxiety and for the improvement of cognition and memory. Using the two‐electrode voltage‐clamp technique, these triterpenes, and some semisynthetic derivatives, were found to exhibit selective negative modulation of different subtypes of the GABA A receptor expressed in Xenopus laevis oocytes. Despite differing by only one hydroxyl group, asiatic acid 1 was found to be a negative modulator of the GABA ‐induced current at α 1 β 2 γ 2L, α 2 β 2 γ 2L and α 5 β 3 γ 2L GABA A receptors, while madecassic acid 2 was not. Asiatic acid 1 exhibited the greatest effect at α 1 β 2 γ 2L ( IC 50 37.05 μ m ), followed by α 5 β 3 γ 2L ( IC 50 64.05 μ m ) then α 2 β 2 γ 2L ( IC 50 427.2 μ m ) receptors. Conversion of the carboxylic acid group of asiatic acid 1 to a carboxamide group (2 α ,3 β ,23‐trihydroxy‐urs‐12‐en‐28‐amide 5 ) resulted in enhanced inhibition at both the α 1 β 2 γ 2L ( IC 50 14.07 μ m ) and α 2 β 2 γ 2L receptor subtypes ( IC 50 28.41 μ m ). The results of this study, and the involvement of α 5 ‐containing GABA A receptors in cognition and memory, suggest that asiatic acid 1 may be a lead compound for the enhancement of cognition and memory.