Premium
Development of Novel 4‐Arylpyridin‐2‐one and 6‐Arylpyrimidin‐4‐one Positive Allosteric Modulators of the M 1 Muscarinic Acetylcholine Receptor
Author(s) -
Jörg Manuela,
Khajehali Elham,
Westhuizen Emma T.,
C. Choy K. H.,
Shackleford David M.,
Tobin Andrew B.,
Sexton Patrick M.,
Valant Celine,
Capuano Ben,
Christopoulos Arthur,
Scammells Peter J.
Publication year - 2021
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.202000540
Subject(s) - allosteric regulation , muscarinic acetylcholine receptor , radioligand , chemistry , allosteric modulator , radioligand assay , acetylcholine , biophysics , receptor , pharmacology , stereochemistry , neuroscience , biochemistry , biology
This study investigated the structure‐activity relationships of 4‐phenylpyridin‐2‐one and 6‐phenylpyrimidin‐4‐one M 1 muscarinic acetylcholine receptor (M 1 mAChRs) positive allosteric modulators (PAMs). The presented series focuses on modifications to the core and top motif of the reported leads, MIPS1650 ( 1 ) and MIPS1780 ( 2 ). Profiling of our novel analogues showed that these modifications result in more nuanced effects on the allosteric properties compared to our previous compounds with alterations to the biaryl pendant. Further pharmacological characterisation of the selected compounds in radioligand binding, IP 1 accumulation and β‐arrestin 2 recruitment assays demonstrated that, despite primarily acting as affinity modulators, the PAMs displayed different pharmacological properties across the two cellular assays. The novel PAM 7 f is a potential lead candidate for further development of peripherally restricted M 1 PAMs, due to its lower blood–brain‐barrier (BBB) permeability and improved exposure in the periphery compared to lead 2 .