CNS-Penetrant Histamine H2 Receptor Biased Agonist as A New Agent for Treating Schizophrenia

摘要

Objective:The histamine H2 receptor(H2R) in medial prefrontal cortex glutamatergic neurons play a crucial role in the pathogenesis of schizophrenia. While H2R agonists can ameliorate MK-801 induced schizophrenia-like symptoms in mice, their therapeutic potential is limited by poor blood-brain barrier(BBB) penetration. Moreover, the distinct pathophysiological functions of H2R-Gs and H2R-β-arrestin(βarr) signaling remain unclear. We aimed to investigate H2R biased signaling and develop a CNS-penetrant biased agonist based on the specific agonist amthamine. Methods and Results: We engineered two biased H2R mutants that selectively activate either Gs or βarr signaling pathways. In H2R knockout mice exhibiting schizophrenialike phenotypes, overexpression of the Gs-biased H2R mutant reversed multiple deficits, including increased locomotor activity, impaired social memory, disrupted social interaction, anhedonia, and cognitive dysfunction, whereas the βarr-biased mutant did not. Furthermore, the Gs-biased mutant restored the reduced excitability of glutamatergic neurons caused by H2R deficiency, which is considered one of the potential mechanisms underlying schizophrenia pathogenesis. Next, we developed an CNS-penetrant H2R agonist, A-03, showed Gs-biased agonism to some extent. which can not only penetrate the blood-brain barrier, but also showed that it can dose-dependently reversed MK-801-induced schizophrenia-like symptoms in mice. Conclusion: Deficits in H2R-Gs signaling, but not βarr signaling, may contribute to schizophrenia pathogenesis. The CNS-penetrant, Gs-biased H2R agonist A-03 effectively reverses schizophrenia-like phenotypes, offering a promising strategy for developing antipsychotic drugs with enhanced efficacy and reduced side effects.

关键词

histamine H2 receptor / biased signaling / schizophrenia