Experimental and Computational Investigation of the Target and Mechanisms of Alkaloids in the Central Nervous System.

has a long history of medicinal use but is also a poisonous plant. Some low-toxicity alkaloids in exhibit anxiolytic, anti-inflammatory, analgesic, and other pharmacological effects; however, certain alkaloids in are highly toxic. Nevertheless, the molecular targets underlying the biological effects of alkaloids remain poorly understood. We employed electrophysiological techniques and molecular modeling to examine the modulatory effects of alkaloids on inhibitory neurotransmitter receptors, as well as to elucidate the mechanisms underlying their molecular interactions. Our findings indicate that low-toxicity alkaloids primarily exert their pharmacological effects through actions on glycine receptors, with the binding site located at the orthosteric site between two α-subunits. Both highly toxic and low-toxicity alkaloids target GABAA receptors, using the β+/α- interface transmembrane structural domains as common binding sites. These results identify the targets through which alkaloids affect the central nervous system and predict the binding modes and key amino acids involved from a computational modeling perspective. However, further experimental validation through mutational studies is necessary to strengthen these findings.