Structure-activity relationship of pyrazol-4-yl-pyridine derivatives and identification of a radiofluorinated probe for imaging the muscarinic acetylcholine receptor M.

There is an accumulating body of evidence implicating the muscarinic acetylcholine receptor 4 (M) in schizophrenia and dementia with Lewy bodies, however, a clinically validated M positron emission tomography (PET) radioligand is currently lacking. As such, the aim of this study was to develop a suitable M PET ligand that allows the non-invasive visualization of M in the brain. Structure-activity relationship studies of pyrazol-4-yl-pyridine derivates led to the discovery of target compound a subtype-selective positive allosteric modulator (PAM).

Cryptic pocket formation underlies allosteric modulator selectivity at muscarinic GPCRs.

Allosteric modulators are highly desirable as drugs, particularly for G-protein-coupled receptor (GPCR) targets, because allosteric drugs can achieve selectivity between closely related receptors. The mechanisms by which allosteric modulators achieve selectivity remain elusive, however, particularly given recent structures that reveal similar allosteric binding sites across receptors. Here we show that positive allosteric modulators (PAMs) of the M1 muscarinic acetylcholine receptor (mAChR) achieve exquisite selectivity by occupying a dynamic pocket absent in existing crystal structures.