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

The recombination of natural product(NP) fragments in unprecedentedways has emerged as an important strategy for bioactive compound discovery.In this context, we propose that privileged primary fragments predictedto be enriched in activity against a specific target class can becoupled to diverse secondary fragments to engineer selectivity amongclosely related targets. Here, we report the synthesis of an alkaloid-inspiredcompound library enriched in spirocyclic ring fusions, comprising58 compounds from 12 tropane- or quinuclidine-containing scaffolds,all of which can be considered pseudo-NPs. The library displays excellentpredicted drug-like properties including high Fsp(3) contentand Lipinski's rule-of-five compliance. Targeted screeningagainst selected members of the serotonin and dopamine G protein-coupledreceptor family led to the identification of several hits that displayedsignificant agonist or antagonist activity against 5-HT2A and/or 5-HT2C, and subsequent optimization of one ofthese delivered a lead dual 5-HT2B/C antagonist with ahighly promising selectivity profile.

Automated summary

The recombination of natural product fragments is an important strategy for discovering bioactive compounds. We synthesized a compound library enriched in spirocyclic ring fusions using alkaloid-inspired scaffolds. The library exhibited excellent drug-like properties and targeted screening led to the identification of hits with significant agonist or antagonist activity against specific serotonin and dopamine receptors. Optimization of one of these hits resulted in a promising lead compound with high selectivity as a dual 5-HT2B/C antagonist.