4.7 Article

Structural optimizations and bioevaluation of N-H aporphine analogues as Gq-biased and selective serotonin 5-HT2C receptor agonists

Journal

BIOORGANIC CHEMISTRY
Volume 123, Issue -, Pages -

Publisher

ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.bioorg.2022.105795

Keywords

Serotonin; 5-HT2C receptor agonist; Aporphine; Functional selectivity; G protein-biased; beta-arrestin recruitment; Antipsychotic

Funding

  1. National Natural Science Foundation of China [22177086, 31971362, 81703330]
  2. Na-tional Program on Key Basic Research Project of China [2018YFA0507004]
  3. National Key Research and Develop-ment Program of China [2021YFE0206000]
  4. Suzhou Municipal Science and Technology Bureau [SYS2020092]
  5. Priority Ac-ademic Program Development of the Jiangsu Higher Education In-stitutes (PAPD, China) [BM2013003]
  6. Jiangsu Key Laboratory of Neuropsychiatric Diseases
  7. National Institute of Mental Health Psychoactive Drug Screening Program (NIMH PDSP) at the Department of Pharmacology, UNC, at Chapel Hill

Ask authors/readers for more resources

The concept of subtype selectivity and functional bias has had a significant impact on GPCR drug discovery. Through synthesis and evaluation, a series of new N-H aporphines were found to be potent and selective 5-HT2C receptor agonists. These agonists with an exclusive bias towards Gq signaling have the potential to be valuable pharmacological tools for understanding therapeutically relevant 5-HT2C signaling pathways and developing alternative antipsychotic medications.
The concept of subtype selectivity and functional bias has recently reshaped current GPCR drug discovery for G protein-coupled receptors. A series of new N -H aporphines with A-ring modifications have been synthesized, and their efficacy on 5-HT2 receptor activation was evaluated. SAR analysis led to the discovery of several more potent and selective 5-HT2C receptor agonists (e.g., 11b and 11f) with low nanomolar activity. Molecular docking analysis of this series of aporphines was in accordance with our SAR results. The functional selectivity of specific compounds was tested via both Gq-mediated calcium flux and beta-arrestin recruitment assays, which revealed that these compounds exhibited no beta-arrestin recruitment activity. Further ADMET study combined with behavioral assessment using a methamphetamine-induced hyperactivity model identified compound 11b and 11f possessing promising drug-like profiles and having antipsychotic potential. These agonists with an exclusive bias toward Gq signaling may serve as valuable pharmacological probes to facilitate the elucidation of therapeutically relevant 5-HT2C signaling pathways and the development of alternative antipsychotic medications.

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