Azepine-Indole Alkaloids From Modulate 5-HT Receptors and Prevent Protein Toxicity in Transgenic .

Nemorosine A () and fargesine (), the main azepine-indole alkaloids of , were explored for their pharmacological profile on neurodegenerative disorders (NDs) applying a combined -- approach. By using and as queries for similarity-based searches of the ChEMBL database, structurally related compounds were identified to modulate the 5-HT receptor; experiments confirmed an agonistic effect for and (24 and 36% at 10 μM, respectively), which might be linked to cognition-enhancing properties. This and the previously reported target profile of and , which also includes BuChE and MAO-A inhibition, prompted the evaluation of these compounds in several models linked to 5-HT modulation and proteotoxicity. On transgenic strain CL4659, which expresses amyloid beta (Aβ) in muscle cells leading to a phenotypic paralysis, and reduced Aβ proteotoxicity by reducing the percentage of paralyzed worms to 51%. Treatment of the NL5901 strain, in which α-synuclein is yellow fluorescent protein (YFP)-tagged, with and (10 μM) significantly reduced the α-synuclein expression. Both alkaloids were further able to significantly extend the time of metallothionein induction, which is associated with reduced neurodegeneration of aged brain tissue. These results add to the multitarget profiles of and and corroborate their potential in the treatment of NDs.