Synthesis and Pharmacological Evaluation of Analogues of Benzyl Quinolone Carboxylic Acid (BQCA) Designed to Bind Irreversibly to an Allosteric Site of the M1 Muscarinic Acetylcholine Receptor

Activation of the M-1 muscarinic acetylcholine receptor (mAChR) is a prospective treatment for alleviating cognitive decline experienced in central nervous system (CNS) disorders. Current therapeutics indiscriminately enhance the activity of the endogenous neurotransmitter ACh, leading to side effects. BQCA is a positive allosteric modulator and allosteric agonist at the M-1 mAChR that has high subtype selectivity and is a promising template from which to generate higher affinity, more pharmacokinetically viable drug candidates. However, to efficiently guide rational drug design, the binding site of BQCA needs to be conclusively elucidated. We report the synthesis and pharmacological validation of BQCA analogues designed to bind irreversibly to the M-1 mAChR. One analogue in particular, 11, can serve as a useful structural probe to confirm the location of the BQCA binding site; ideally, by co-crystallization with the M-1 mAChR. Furthermore, this ligand may also be used as a pharmacological tool with a range of applications.