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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 DC Dexter C , Bungard JD Joseph D , Chang S Sichen , Rodriguez AL Alice L , Blobaum AL Annie L , Boutaud O Olivier , Melancon BJ Bruce J , Niswender CM Colleen M , Jeffrey Conn P P , Lindsley CW Craig W .
Bioorganic & medicinal chemistry letters. 2020 11 27; 32().
127724

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