Here we describe the synthesis and molecular tuning of a heterocyclic hinge to switch between agonist and antagonist ligand conformations in order to activate or inhibit a G protein coupled receptor (GPCR). Incorporation of a heterocycle into small molecules confers rigidity, often solubility, and can direct conformation that leads to bioactive compounds. The switch relies upon the heteroatom interacting, or not, intramolecularly with an adjacent carboxamide substituent. Here we choose a GPCR on the surface of human immune cells to demonstrate the use of different heterocycles to control pro- versus anti-inflammatory activity at the cellular and animal model levels. The latest chemical manipulation of this switch through new synthetic approaches, the resulting structures, and impact on activity will be described.

Heterocycles for switching GPCR ligand conformation and activity

2019 Spring National Meeting

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