Ibogalogs induce antiseizure activity in rodents by a mechanism involving 5-HT2A/2C receptor activation with a major role of 5-HT2A receptors in the hippocampal CA3 subfield

Abdeslam Chagraoui, Paulina Kazmierska-Grebowska, Olivia Byache, Alejandro Abraham, Deborah Rudin, Bartosz Caban, Tomasz Kowalczyk, Matthias E. Liechti, Daniel Wacker, Chloé Aman, Philippe De Deurwaerdère, Hugo R. Arias
Biochemical Pharmacology. 2026-05-01; 247: 117799
DOI: 10.1016/j.bcp.2026.117799

Chagraoui A(1), Kazmierska-Grebowska P(2), Byache O(3), Abraham A(4), Rudin D(5), Caban B(2), Kowalczyk T(2), Liechti ME(5), Wacker D(4), Aman C(3), Deurwaerdère P(3), Arias HR(6).

Author information:
(1)Laboratory Nordic: Neuroendocrine, endocrine and germinal differentiation
communication – UMR 1239 (Inserm), Normandy University, UNIROUEN, Institute for
Research and Innovation in Biomedicine of Normandy (IRIB), Rouen, France;
Department of Medical Biochemistry, Rouen University Hospital, CHU de Rouen,
France. Electronic address: .
(2)Department of Neurobiology, Faculty of Biology and Environmental Protection,
University of Lodz, Lodz, Poland.
(3)Centre National de la Recherche Scientifique, Institut des Neurosciences
Intégratives et Cognitives d’Aquitaine, UMR 5287, Bordeaux, France.
(4)Department of Pharmacological Sciences and Department of Neuroscience, Icahn
School of Medicine at Mount Sinai, New York, NY, USA.
(5)Division of Clinical Pharmacology and Toxicology, Department of
Pharmaceutical Sciences, University of Basel, Basel, Switzerland; Division of
Clinical Pharmacology and Toxicology, Department of Biomedicine, University
Hospital Basel and University of Basel, Basel, Switzerland.
(6)Department of Pharmacology and Physiology, Oklahoma State University College
of Osteopathic Medicine, Tahlequah, OK, USA.

The antiseizure properties of ibogalogs, including ibogaminalog (DM506),
ibogainalog (IBG), and nor-IBG, were assessed in rodents using the
pentylenetetrazol (PTZ)-induced seizure test. The behavioral findings indicated
that ibogalogs exhibited mild acute antiseizure effects in mice, with endpoint-
and time window-dependent differences between the compounds. The antiseizure
effect was suppressed by volinanserin and SB242084, consistent with the
involvement of 5-HT2A and 5-HT2C receptors. The antiseizure activity after
repeated administration (7 and 14 days) of subthreshold doses of nor-IBG
(3 mg/kg) or DM506 (5 mg/kg) was higher than that after acute treatment,
indicating augmented efficacy. Subthreshold doses of DM506 and nor-IBG restored
the impact of PTZ on monoamine levels in hippocampal tissue following repeated
administration, but not after a single dose. Additionally, the influence of
ibogalogs was evaluated on epileptiform discharges induced by kainic acid (KA)
in the CA3 region of the hippocampus. The results showed that nor-IBG and DM506
decreased epileptiform discharges in a concentration-dependent manner. Nor-IBG
activity was inhibited by volinanserin, supporting a role for the 5-HT2AR.
Functional studies have shown that ibogalogs are more potent agonists at
5-HT2A/2CRs than at 5-HT1A/1BRs, supporting the role of 5-HT2AR. In conclusion,
repetitive treatment with ibogalogs induced antiseizure activity in mice through
5-HT2A/2CR activation, accompanied by normalization of PTZ-induced alterations
in hippocampal monoamines. In the hippocampal CA3 subfield, ibogalogs reduced
KA-induced epileptiform discharges, where nor-IBG activity was mediated by
5-HT2AR activation.

DOI: 10.1016/j.bcp.2026.117799
PMID: 41690414

Conflict of interest statement: Declaration of competing interest The authors
declare that they have no known competing financial interests or personal
relationships that could have appeared to influence the work reported in this
paper.