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 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.