Abstract Details

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-HT_2B and 5-HT_2A, 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-HT_2B and 5-HT_2A 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-HT_2B and 5-HT_2A human recombinant G protein-coupled receptors using a CHO-K1-mt aequorin G_α16 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-HT_2B receptor (from agonist to antagonist) agreed with their ranking by risk of fibrosis. All nine tested compounds were full agonists at 5-HT_2A.

Across nine major ergot alkaloids, the degree of agonism at 5-HT_2B matched the tendency to cause fibrosis, a major liability of some of these compounds.  All of the compounds were agonists at the 5-HT_2A 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.