Lead optimization of the VU0486321 series of mGlu 1 PAMs. Part 4: SAR reveals positive cooperativity across multiple mGlu receptor subtypes leading to subtype unselective PAMs

• Published in: Bioorganic & medicinal chemistry letters Vol. 32; pp. 127724 - 127727
• Main Authors: Davis, Dexter C., Bungard, Joseph D., Chang, Sichen, Rodriguez, Alice L., Blobaum, Annie L., Boutaud, Olivier, Melancon, Bruce J., Niswender, Colleen M., Conn, P. Jeffrey, Lindsley, Craig W.
• Format: Journal Article
• Language: English
• Published: OXFORD Elsevier 15.01.2021
• Subjects: Chemistry; Chemistry, Medicinal; Chemistry, Organic; Life Sciences & Biomedicine; Pharmacology & Pharmacy; Physical Sciences; Science & Technology; mGlu; Positive allosteric modulator (PAM); GPCRS; IN-VIVO; NEGATIVE ALLOSTERIC MODULATOR; OPPORTUNITIES; Structure-activity-relationship (SAR); Metabotropic glutamate receptor; DISCOVERY; SCAFFOLD
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2020.127724

Further optimization of the VU0486321 series of highly selective and CNS-penetrant mGlu1 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 (mGlu1/5) and Group III (mGlu4/6/7/8) 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 mGlu1/4/7/8 PAMs, as well as the first report of a GPCR allosteric 'privileged structure'.