Bioactivity guided isolation of antipsychotic constituents from the leaves of Rauwolfia tetraphylla L.

This study was undertaken to ascertain the antipsychotic properties of Rauwolfia tetraphylla L leaves and to isolate and characterize the antipsychotic constituents. Among the MeOH extract and some alkaloidal fractions at different pHs, the alkaloidal CHCl3 fraction at pH-9 (2C) showed the highest antipsychotic activity against dopaminergic (DA-D-2) and serotonergic (5-HT2A) receptors in-vitro and amphetamine induced hyperactive mouse model in-vivo. The activity guided isolation of CHCl3 fraction (2C) afforded six indole alkaloids: 10-methoxytetrahydroalstonine (1), isoreserpiline (2), an isomeric mixture of 11-demethoxyreserpiline (3) and 10-demethoxyreserpiline (4), a-yohimbine (5) and reserpiline (6). Given orally, alkaloids 3-6 showed significant antipsychotic activity in a dose dependent manner. None of the extract, alkaloidal fractions or alkaloids showed any extra pyramidal symptoms at the tested doses. It was also observed that MeOH extract was behaving similar to other clinically used novel atypical antipsychotics in having 5-HT2A occupancy greater than the DA-D2 receptor at the tested doses. Further toxicity and safety evaluation studies of Me0H extracts of R. tetraphylla leaves at different doses (10, 100, 300 and 2000 mg/kg) on female Swiss albino mice showed that Me0H extract is non toxic. The isolated alkaloids, 3-6 could serve as a promising lead structure for drug development of treating psychotic conditions in human. (C) 2012 Elsevier B.V. All rights reserved.