Journal
CHEMMEDCHEM
Volume 16, Issue 1, Pages 216-233Publisher
WILEY-V C H VERLAG GMBH
DOI: 10.1002/cmdc.202000540
Keywords
allosteric ligands; modulators; muscarinic acetylcholine receptor
Categories
Funding
- Australian Research Council (ARC) [DP110100687]
- National Health and Medicinal Research Council (NHMRC) of Australia [APP1055134, APP1049564]
- Wellcome Trust Collaborative Research Award [201529Z16Z]
- NHMRC [GNT1013819]
Ask authors/readers for more resources
This study investigated the structure-activity relationships of 4-phenylpyridin-2-one and 6-phenylpyrimidin-4-one M(1)muscarinic acetylcholine receptor positive allosteric modulators (PAMs), showing that modifications to the analogues result in nuanced effects on the allosteric properties. The research also found that despite primarily acting as affinity modulators, the PAMs displayed different pharmacological properties across the two cellular assays. The novel PAM7 was identified as a potential lead candidate for further development due to its lower BBB permeability and improved exposure in the periphery compared to lead2.
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 beta-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 PAM7 fis 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 lead2.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available