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Abstract Details

Serotonin Receptor Activity Profiles for Nine Commercialized Ergot Alkaloids Correspond to Known Risks of Fibrosis and Hallucinations
General Neurology
P6 - Poster Session 6 (12:00 PM-1:00 PM)
6-006

The universal skeleton of the ergot alkaloids – the 4-ring ergoline nucleus – contains the essential structural elements found in the neurotransmitters dopamine, serotonin, and epinephrine. As a result, the ergot alkaloids have a propensity to interact with numerous neurotransmitter receptors. While some such interactions are necessary for a compound to have particular desired effects, others may be associated with adverse effects.

Receptor activities at two serotonin receptors, 5-HT2B and 5-HT2A, are of specific interest due to the close association of agonism at these receptors with fibrotic and hallucinogenic adverse events, respectively.

Using novel receptor behavior mapping techniques, Xoc generated 5-HT2B and 5-HT2A neuroreceptor activity profiles for nine historically marketed ergot alkaloid compounds. The profiles were evaluated against the known fibrotic and hallucinogenic liabilities of the compounds.

To generate receptor activity profiles for marketed ergot alkaloid compounds and evaluate the profiles against known fibrotic and hallucinogenic liabilities of the compounds.

Compounds were tested on 5-HT2B and 5-HT2A human recombinant G protein-coupled receptors using a CHO-K1-mt aequorin Gα16 cell line at Euroscreen laboratory, Belgium with IP-One assays using an αMe-5-HT reference agonist and a ketanserin reference antagonist. Sample dose response curves were generated to determine EC50/IC50 and relative degree of agonist/antagonist responses.

The ranking of the test compounds by relative response at the 5-HT2B receptor (from agonist to antagonist) agreed with their ranking by risk of fibrosis. All nine tested compounds were full agonists at 5-HT2A.

Across nine major ergot alkaloids, the degree of agonism at 5-HT2B matched the tendency to cause fibrosis, a major liability of some of these compounds.  All of the compounds were agonists at the 5-HT2A receptor, in line with their history of posing a risk of hallucinations. Novel compounds, free of these effects, could confer substantial safety advantages over existing compounds.

Authors/Disclosures
Robert Fishman, MD (Butler Hospital )
PRESENTER
Dr. Fishman has nothing to disclose.
Miguel Guzman No disclosure on file
on Behalf of the CLASSIC-MS Steering Committee No disclosure on file
Scott *use 337644 Borland No disclosure on file
Matthew Leyden No disclosure on file
Alan M. Rapoport, MD, FAAN Dr. Rapoport has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for AbbVie, Amgen, Biohaven, Cala Health, Satsuma, Teva Pharmaceutical Industries, Theranica, Xoc and Zosano. Dr. Rapoport has received personal compensation in the range of $10,000-$49,999 for serving on a Speakers Bureau for AbbVie, Amgen, Biohaven, Lundbeck and Teva Pharmaceutical Industries. Dr. Rapoport has received personal compensation in the range of $10,000-$49,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for Neurology Reviews.