Discovery of VU6005649, a CNS Penetrant mGlu_7/8 Receptor PAM Derived from a Series of Pyrazolo[1,5‑<i>a</i>]pyrimidines

Herein, we report the structure–activity relationships within a series of mGlu₇ PAMs based on a pyrazolo­[1,5-<i>a</i>]­pyrimidine core with excellent CNS penetration (<i>K</i>_ps > 1 and <i>K</i>_p,uus > 1). Analogues in this series proved to display a range of Group III mGlu receptor selectivity, but VU6005649 emerged as the first dual mGlu_7/8 PAM, filling a void in the Group III mGlu receptor PAM toolbox and demonstrating <i>in vivo</i> efficacy in a mouse contextual fear conditioning model