VU6005649

Herein, we report the structure-activity relationships within a series of mGlu₇ PAMs based on a pyrazolo[1,5-a]pyrimidine core with excellent CNS penetration (K_ps > 1 and K_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 in vivo efficacy in a mouse contextual fear conditioning model.

Metabotropic glutamate receptor 7 (mGlu₇) is a G protein coupled receptor that has demonstrated promise as a therapeutic target across a number of neurol. and psychiatric diseases.Compounds that modulate the activity of mGlu7, such as pos. and neg. allosteric modulators, may represent new therapeutic strategies to modulate receptor activity.The endogenous neurotransmitter associated with the mGlu receptor family, glutamate, exhibits low efficacy and potency in activating mGlu7, and surrogate agonists, such as the compound L-(+)-2-Amino-4-phosphonobutyric acid (L-AP4), are often used for receptor activation and compound profiling.To understand the implications of the use of such agonists in the development of pos. allosteric modulators (PAMs), we performed a systematic evaluation of receptor activation using a system in which mutations can be made in either protomer of the mGlu7 dimer; we employed mutations that prevent interaction with the orthosteric site as well as the G-protein coupling site of the receptor.We then measured increases in calcium levels downstream of a promiscuous G protein to assess the effects of mutations in one of the two protomers in the presence of two different agonists and three pos. allosteric modulators.Our results reveal that distinct PAMs, for example N-[3-Chloro-4-[(5-chloro-2-pyridinyl)oxy]phenyl]-2-pyridinecarboxamide (VU0422288) and 3-(2,3-Difluoro-4-methoxyphenyl)-2,5-dimethyl-7-(trifluoromethyl)pyrazolo[1,5-a]pyrimidine (VU6005649), do exhibit different maximal levels of potentiation with L-AP4 vs. glutamate, but there appear to be common stable receptor conformations that are shared among all of the compounds examined here.