Neuronal ion channel modulation by Drimys winteri compounds: Opening a new chemical space to neuropharmacology

Numerous pathological states of the nervous system involve alterations in neuronal excitability and synaptic dysfunction, which depend on the function of ion channels. Due to their critical involvement in health and disease, the search for new compounds that modulate these proteins is still relevant. Traditional medicine has long been a rich source of neuroactive compounds. For example, the indigenous Mapuche people have used the leaves and bark of the Drimys winteri tree for centuries to treat various diseases. Consequently, several studies have investigated the biological effects of compounds in Drimys winteri , highlighting sesquiterpenes such as α-humulene, drimenin, polygodial, and α-, β-, γ-eudesmol. However, there is currently no literature review focusing on the ability of these sesquiterpenes to modulate ion channels. This review summarizes the current knowledge about neuroactive compounds found in Drimys winteri , with special emphasis on their direct actions on neuronal ion channels. Several Drimys winteri sesquiterpenes modulate a diverse array of neuronal ion channels, including transient receptor potential channels, gamma-aminobutyric acid A receptors, nicotinic acetylcholine receptors, and voltage-dependent Ca 2+ and Na + channels. Interestingly, the modulation of these molecular targets by Drimys winteri sesquiterpenes correlates with their therapeutic actions. The promiscuous pharmacological profile of Drimys winteri sesquiterpenes suggests they modulate multiple protein targets in vivo , making them potentially useful for treating complex, multifactorial diseases. Further studies at the molecular level may aid in developing multi-targeted drugs with enhanced therapeutic effects.