Allosteric modulation of muscarinic acetylcholine receptors (mAChRs) in physiopathology.

The muscarinic acetylcholine receptors (mAChRs) are involved in most of the major debilitating disorders, peripherally such as asthma, heart diseases, but also centrally such as Alzheimer’s, Parkinson’s and Schizophrenia. Despite their critical physiopathological importance, much remains to be learned about the regulation of these receptors by small, drug-like, molecules. To date, the key outcome of our research is the topographical and pharmacological characterisation of secondary, allosteric binding pockets at mAChRs, a prototypical family A G protein-coupled receptor (GPCR).

Our hypothesis is that these allosteric sites may represent an untapped avenue for more selective GPCR signalling than is currently attainable via the traditional orthosteric binding site.

We are focusing on two main fronts:
1. the generation of synthetic allosteric ligands to elucidate their modes and mechanisms of binding to mAChR, whereby using medicinal chemistry we are generating novel allosteric tools that are pharmacologically assessed in both recombinant and native systems, and
2. the existence of putative endogenous allosteric ligands and their implication in life-threatening diseases, including asthma, or myocarditis.