Lead optimization of the VU0486321 series of mGlu PAMs. Part 4: SAR reveals positive cooperativity across multiple mGlu receptor subtypes leading to subtype unselective PAMs
AUTHORS
Davis
DCDexter C ,
Bungard
JDJoseph D ,
Chang
SSichen ,
Rodriguez
ALAlice L ,
Blobaum
ALAnnie L ,
Boutaud
OOlivier ,
Melancon
BJBruce J ,
Niswender
CMColleen M ,
Jeffrey Conn
PP ,
Lindsley
CWCraig W .
Bioorganic & medicinal chemistry letters. 2020 11 27; 32().
127724
- PMID: 33253881[PubMed].
ABSTRACT
Further optimization of the VU0486321 series of highly selective and CNS-penetrant mGlu PAMs identified unique ‘molecular switches’ on the central aromatic ring that engendered positive cooperativity with multiple mGlu subtypes across the receptor family, resulting in compounds with comparable activity at Group I (mGlu) and Group III (mGlu) mGlu receptors, receptors. These exciting data suggests this PAM chemotype appears to bind to multiple mGlu receptors, and that subtype selectivity is dictated by the degree of cooperativity, not a subtype selective, unique allosteric binding site. Moreover, there is interesting therapeutic potential for mGlu PAMs, as well as the first report of a GPCR allosteric ‘privileged structure’.
Tags: 2020