Dualsteric Ligands

Dualsteric (or bitopic) ligands represent a novel mode of targeting G protein-coupled receptors (GPCRs). These compounds attach simultaneously to the orthosteric binding site and an additional allosteric binding area of the receptor protein.

This approach allows the exploitation of favourable characteristics of the orthosteric and the allosteric site by a single molecule. The orthosteric interaction enables high affinity binding and activation of the receptor. The allosteric interaction can provide with receptor subtype-selectivity and, in addition, may modulate efficacy and intracellular signalling pathway activation.

We design and synthesize dualsteric ligands of acetylcholine muscarinic receptors (mAChRs) via molecular hybridization of orthosteric agonists and allosteric modulators. In addition to a potential therapeutic use thanks to their ability to fine-tune the cellular responses mediated by mAChRs, these molecules can be used as valuable research tools for a label-free approach to gain deeper insight into the geometry of activation-related conformational changes of GPCRs.

dualsteric ligands

Selected Publications