8 September 2025
Metabotropic glutamate receptor 1 (mGluR1), primarily expressed in cortico-striatal and thalamo-striatal circuits, plays a critical role in regulating intracellular calcium signaling and endocannabinoid release. These mechanisms inhibit dopamine release via CB2 receptors. Positive allosteric modulators (PAMs) of mGluR1 have been shown to inhibit dopamine release and exhibit antipsychotic-like effects in pre-clinical in vivo models through endocannabinoid-dependent pathways. Additionally, mGluR1 PAMs restore cortical inhibitory tone and improve cognitive performance in models of NMDA receptor hypofunction.
Human genetic studies have linked loss-of-function single nucleotide polymorphisms (SNPs) in the GRM1 gene to schizophrenia, and in vitro studies have demonstrated that mGluR1 PAMs can restore signaling in mutant receptors associated with these genetic variants. By reducing cortical hyperactivity and re-establishing excitatory/inhibitory balance in the prefrontal cortex in preclinical models, mGluR1 PAMs may represent a promising concept for addressing schizophrenia symptoms, cognitive deficits, and related indications.
To support your research on mGluR1, we are offering two highly selective PAMs - BI02982816 and BI-1752 - free of charge via opnMe. In a preclinical experimental context, these molecules have demonstrated the ability to normalize hyperdopaminergic states, reverse cognitive deficits, and restore function in mutant receptors linked to schizophrenia, all without impairing motivation or cognition. To ensure robust experimental design, we also provide BI-4066, a structurally similar but inactive analogue, as a negative control. Researchers can use these compounds to investigate the roles of mGluR1 in vitro and in vivo.
Interested researchers will receive the molecules free of charge and retain full ownership of their results. We encourage you to publish your findings as part of our commitment to open science.
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About BI02982816 and BI-1752:
BI02982816 is a selective, CNS-penetrant mGluR1 PAM with an in vitro EC50 of 54 nM on human and 46 nM on rat. It demonstrates good brain exposure at 3 mg/kg in rats (free brain concentration of 32 nM, ~0.6× EC50) and tolerable dose escalation to 10 mg/kg (67 nM, ~1.2× EC50).
BI-1752, with an improved CYP450 profile and high CNS penetration, achieves a free brain concentration of 80 nM (~0.74× EC50) at 10 mg/kg in rats but shows adverse effects at 30 mg/kg (579 nM, ~5.2× EC50), limiting further escalation. Both compounds exhibit acceptable DMPK profiles and good brain exposure at effective doses.
About opnMe:
opnMe.com, the open innovation portal of Boehringer Ingelheim, fosters science and collaboration initiatives in areas of high unmet medical need. As part of our first pillar, the “Molecules to Order”, we share well-characterized tool compounds free of charge with no IP strings attached. With our “opn2EXPERTS” and “techMATCH” programs, we enlist scientific advice on key biologic issues to fuel further drug discovery and deliver novel solutions that benefit unmet patient needs. Our opn2TALENTS PostDoc grants, provide an opportunity for high-caliber talents to pitch their scientific approaches for well-defined research questions to conduct their research at one of our discovery research sites.