Identification of 5-HT2 Serotonin Receptor Modulators through the Synthesis of a Diverse, Tropane- and Quinuclidine-alkaloid-Inspired Compound Library

Research output: Contribution to journalJournal articleResearchpeer-review

The recombination of natural product (NP) fragments in unprecedented ways has emerged as an important strategy for bioactive compound discovery. In this context, we propose that privileged primary fragments predicted to be enriched in activity against a specific target class can be coupled to diverse secondary fragments to engineer selectivity among closely related targets. Here, we report the synthesis of an alkaloid-inspired compound library enriched in spirocyclic ring fusions, comprising 58 compounds from 12 tropane- or quinuclidine-containing scaffolds, all of which can be considered pseudo-NPs. The library displays excellent predicted drug-like properties including high Fsp3 content and Lipinski's rule-of-five compliance. Targeted screening against selected members of the serotonin and dopamine G protein-coupled receptor family led to the identification of several hits that displayed significant agonist or antagonist activity against 5-HT2A and/or 5-HT2C, and subsequent optimization of one of these delivered a lead dual 5-HT2B/C antagonist with a highly promising selectivity profile.

Original languageEnglish
JournalJournal of Medicinal Chemistry
Issue number16
Pages (from-to)11536-11554
Publication statusPublished - 2023

    Research areas

  • Alkaloids/pharmacology, Receptor, Serotonin, 5-HT2A, Receptor, Serotonin, 5-HT2C, Receptors, Serotonin, Serotonin, Serotonin 5-HT2 Receptor Agonists/pharmacology, Serotonin 5-HT2 Receptor Antagonists/pharmacology, Tropanes, Quinuclidines/chemistry

ID: 365597915