Pérez, SheilaVale González, María del CarmenAlonso, EvaFuwa, HaruhikoSasaki, MakotoKonno, YuGoto, TomomiSuga, YutoRodríguez Vieytes, MercedesBotana López, Luis Miguel2026-05-202026-05-202012-08-15Pérez S, Vale C, Alonso E, Fuwa H, Sasaki M, Konno Y, Goto T, Suga Y, Vieytes MR, Botana LM. Effect of gambierol and its tetracyclic and heptacyclic analogues in cultured cerebellar neurons: a structure-activity relationships study. Chem Res Toxicol. 2012 Sep 17;25(9):1929-37. doi: 10.1021/tx300242m. Epub 2012 Aug 29. PMID: 22894724.https://hdl.handle.net/10347/47310This document is the Accepted Manuscript version of a Published Article that appeared in final form in Chemical Research in Toxicology, copyright © 2012 American Chemical Society. To access the final published article, see https://doi.org/10.1021/tx300242mThe polycyclic ether class of marine natural products has attracted the attention of researchers due to their complex and large chemical structures and diverse biological activities. Gambierol is a marine polycyclic ether toxin, first isolated along with ciguatoxin congeners from the dinoflagellate Gambierdiscus toxicus. The parent compound gambierol and the analogues evaluated in this work share the main crucial elements for biological activity, previously described to be the C28═C29 double bond within the H ring and the unsaturated side chain [Fuwa, H., Kainuma, N., Tachibana, K., Tsukano, C., Satake, M., and Sasaki, M. (2004) Diverted total synthesis and biological evaluation of gambierol analogues: Elucidation of crucial structural elements for potent toxicity. Chem. Eur. J.10, 4894−4909]. With the aim to gain a deeper understanding of the cellular mechanisms involved in the biological activity of these compounds, we compared its activity in primary cultured neurons. The three compounds inhibited voltage-gated potassium channels (Kv) in a concentration-dependent manner and with similar potency, caused a small inhibition of voltage-gated sodium channels (Nav), and evoked cytosolic calcium oscillations. Moreover, the three compounds elicited a “loss of function” effect on Kv channels at concentrations of 0.1 nM. Additionally, both the tetracyclic and the heptacyclic derivatives of gambierol elicited synchronous calcium oscillations similar to those previously described for gambierol in cultured cerebellar neurons. Neither gambierol nor its tetracyclic derivative elicited cell toxicity, while the heptacyclic analogue caused a time-dependent decrease in cell viability. Neither the tetracyclic nor the heptacyclic analogues of gambierol exhibited lethality in mice after ip injection of 50 or 80 μg/kg of each compound. Altogether, the results presented in this work support an identical mechanism of action for gambierol and its tetracyclic and heptacyclic analogues and indicate a “loss of function” effect on potassium channels even after administration of the three compounds at subnanomolar concentrations. In addition, because gambierol is known to stabilize the closed state of Kv3 channels, the results presented in this paper may have implications for understanding of channel functions and for future development of therapies against ciguatera poisoning and potassium channel-related diseases.engGambierolVoltage-gated K+ channelsVoltage-gated Na+ channelCalcium oscillationsCytotoxicityCerebellar granule cellInvestigaciónjournal article10.1021/tx300242m0893-228Xopen access