Selective Gq Protein Partial Agonists and Beta-arrestin-biased 5-HT2A Receptor Agonists with Utility in Various Disorders

Unmet Need

Serotonergic psychedelics like psilocybin and LSD are known to possess considerable therapeutic potential. They exhibit impressive clinical promise for the treatment of inflammatory disease, substance use disorders, psychiatric disorders, and various neurological conditions. However, there are significant challenges, as these drugs are limited by their hallucinogenic effects, which requires close clinical supervision and can cause confusion and anxiety for some patients.

There is a pressing need to develop new agents that retain the therapeutic effects similar to existing serotonergic psychedelic compounds but are less prone to induce hallucinogenic activity.

Opportunity

The Wallach lab has invented novel selective 5-HT_2A receptor ligands that act as Gq protein partial agonists as well as functionally selective or biased beta-arrestin agonists. Gq agonism has been found to be responsible for the hallucinogenic effects of psychedelic 5-HT_2A receptor agonists. Partial Gq agonists are able to stimulate the Gq signaling pathway below the threshold required to induce hallucinogenic action. By activating this pathway such ligands have potential in indications targeted by existing psychedelics. Partial agonists have been highly effective therapeutics in other fields including opioids and D2 antagonist antipsychotics.

The beta-arrestin biased 5-HT_2A agonists selectively activate the beta-arrestin signaling pathway over the Gq pathway. Beta-arrestins regulates receptor signaling, desensitization, and internalization. By blocking 5-HT2A receptor Gq activation and stimulating desensitization and internalization beta-arrestin biased 5-HT_2A receptor ligands show promise in indications conventionally targeted by 5-HT_2A receptor antagonists (e.g., antipsychotics) but with anticipated clinical improvements in efficacy and tolerability.

Existing 5-HT_2A agonists lack selectivity over the closely related 5-HT_2B receptor. 5-HT_2B agonism is implicated in cardiac toxicity. Importantly, these novel compounds possess functional selectivity for 5-HT_2A over the 5-HT_2B receptors. Accordingly, the novel selective 5-HT_2A receptor ligands have therapeutic potential without hallucinogenic effects and cardiac toxicity risk. Obtaining such selectivity has been a long-standing challenge and significantly de-risks these compounds.