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

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.

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 (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 the 5-HT_2A receptor.

Across nine major ergot alkaloids, the degree of agonism at the 5-HT_2B receptor 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.