Selective, Gq Protein Partial Agonists, and Beta-arrestin-biased 5-HT2A Receptor Agonists with Utility in Various Disorders
Lead Inventors
Jason V. Wallach, PhD, Assistant Professor, Department of Pharmaceutical Sciences
John McCorvy, PhD, Associate Professor, Medical College of Wisconsin
Adam L. Halberstadt, PhD, Adjunct Professor, University of California, San Diego
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-HT2A 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-HT2A 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-HT2A 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-HT2A receptor ligands show promise in indications conventionally targeted by 5-HT2A receptor antagonists (e.g., antipsychotics) but with anticipated clinical improvements in efficacy and tolerability.
Existing 5-HT2A agonists lack selectivity over the closely related 5-HT2B receptor. 5-HT2B agonism is implicated in cardiac toxicity. Importantly, these novel compounds possess functional selectivity for 5-HT2A over the 5-HT2B receptors. Obtaining such selectivity has been a long-standing challenge and significantly de-risks these compounds.
They have therapeutic potential without hallucinogenic effects and cardiac toxicity risk.
Unique Attributes
- Potent 5-HT2A receptor selective Gq partial agonists devoid of hallucinogenic effects
- Potent 5-HT2A receptor selective beta-arrestin biased agonists devoid of hallucinogenic effects
- Excellent 5-HT2A receptor selectivity with functional selectivity over the 5-HT2B receptor; reduced cardiac toxicity risk
Clinical Applications
Treatment of psychosis, schizophrenia, major depressive disorder, anxiety disorders, substance use disorders, cluster headaches, chronic pain disorders, and sleep disorders.
Stage of Development
Extensive in vitro pharmacological characterizations and in vivo testing in rodent models.
Intellectual Property
Patent published November 2022: WO 2022241006 A1
US application published as US 2024/0254087 A1, August 2024.
EP application published as EP4337220 A4, July 2025.
CA application published as CA3217737 A1, November 2022.
Collaboration or Licensing Opportunity
Actively seeking licensees for commercialization or collaboration to complete preclinical studies.
Publications
- Wallach et al. Identification of 5-HT2A receptor signaling pathways associated with psychedelic potential. Nature Communications. 2023 Dec 15;14(1):8221.