Author: Haymer, Daniel H. ; Quitalig, Marc ; Blobaum, Annie L. ; Voehringer, Patrizia ; Ursu, Daniel ; Reed, Carson W. ; Lindsley, Craig W. ; Niswender, Colleen M. ; Spearing, Paul K. ; Schuelert, Niklas ; Cho, Hyekyung P. ; Rook, Jerri M. ; Priepke, Henning ; Trombley, Trevor A. ; Kalbfleisch, Jacob F. ; Sarwar, Mohammad Moshin ; Boutaud, Olivier ; Turkett, Jeremy A. ; Melancon, Bruce J. ; Nastase, Anthony F. ; Dickerson, Jonathan W. ; Conn, P. Jeffrey

Herein, we report progress toward a metabotropic glutamate receptor subtype 1 (mGlu₁) positive allosteric modulator (PAM) clinical candidate and the discovery of VU6024578/BI02982816. From a weak high-throughput screening hit (VU0538160, EC₅₀ > 10 μM, 71% Glu_max), optimization efforts improved functional potency over 185-fold to deliver the selective (inactive on mGlu_2-5,7,8) and CNS penetrant (rat K_p = 0.99, K_p,uu = 0.82; MDCK-MDR1 ER = 1.7, P_app = 73 × 10-6 cm/s) mGlu₁ PAM (VU6024578/BI02982816, EC₅₀ = 54 nM, 83% Glu_max). An excellent rat pharmacokinetic profile allowed the evaluation of VU6024578/BI02982816 in both amphetamine-induced hyperlocomotion (minimum effective dose (MED) = 3 mg/kg, p.o.) and MK-801 induced disruptions of novel object recognition (MED = 10 mg/kg p.o.), thus providing efficacy in preclinical models of psychosis and cognition. However, unanticipated AEs in dog prevented further consideration as a candidate. Thus, VU6024578/BI02982816 can serve as a best-in-class in vivo rodent tool to study selective mGlu₁ activation.

01 Sep 2022·Neuropsychopharmacology

mGlu1-mediated restoration of prefrontal cortex inhibitory signaling reverses social and cognitive deficits in an NMDA hypofunction model in mice

Article

Author: Niswender, Colleen M ; Gallinger, Isabel M ; Foster, Daniel J ; Luessen, Deborah J ; Conn, P Jeffrey ; Melancon, Bruce J ; Ferranti, Anthony S ; Lindsley, Craig W

Extensive evidence supports the hypothesis that deficits in inhibitory GABA transmission in the prefrontal cortex (PFC) may drive pathophysiological changes underlying symptoms of schizophrenia that are not currently treated by available medications, including cognitive and social impairments. Recently, the mGlu₁ subtype of metabotropic glutamate (mGlu) receptor has been implicated as a novel target to restore GABAergic transmission in the PFC. A recent study reported that activation of mGlu₁ increases inhibitory transmission in the PFC through excitation of somatostatin-expressing GABAergic interneurons, implicating mGlu₁ PAMs as a potential treatment strategy for schizophrenia. Here, we leveraged positive allosteric modulators (PAMs) of mGlu₁ to examine whether mGlu₁ activation might reverse physiological effects and behavioral deficits induced by MK-801, an NMDA receptor antagonist commonly used to model cortical deficits observed in schizophrenia patients. Using ex vivo whole-cell patch-clamp electrophysiology, we found that MK-801 decreased the frequency of spontaneous inhibitory postsynaptic currents onto layer V pyramidal cells of the PFC and this cortical disinhibition was reversed by mGlu₁ activation. Furthermore, acute MK-801 treatment selectively induced inhibitory deficits onto layer V pyramidal cells that project to the basolateral amygdala, but not to the nucleus accumbens, and these deficits were restored by selective mGlu₁ activation. Importantly, the mGlu₁ PAM VU6004909 effectively reversed deficits in sociability and social novelty preference in a three-chamber assay and improved novel objection recognition following MK-801 treatment. Together, these findings provide compelling evidence that mGlu₁ PAMs could serve as a novel approach to reduce social and cognitive deficits associated with schizophrenia by enhancing inhibitory transmission in the PFC, thus providing an exciting improvement over current antipsychotic medication.

01 May 2022·The FASEB Journal

Selective mGlu₁ Potentiation Reverses Cortical Disinhibition and Schizophrenia‐like Social and Cognitive Deficits

Article

Author: Luessen, Deborah ; Gallinger, Isabel G. ; Conn, Jeffrey

There is a critical need to develop novel therapeutic strategies for addressing the negative and cognitive symptom domains in schizophrenia (SCZ). Multiple clinical and preclinical studies support the hypothesis that loss of GABAergic inhibitory transmission in the prefrontal cortex (PFC) and other forebrain regions may play a critical role in the pathophysiological changes underlying cognitive and social behavioral deficits in SCZ patients. Recently, we demonstrated that activation of the mGlu1 subtype of metabotropic glutamate receptor increases inhibitory transmission in the PFC by selective excitation of somatostatin‐expressing GABA interneurons. Genetic studies in humans reveal an association between deleterious non‐synonymous single nucleotide polymorphisms (nsSNPS) in of the human gene encoding mGlu1 (GRM1) and SCZ, raising the possibility that mGlu1 signaling is critical to the function of brain circuits underlying symptoms associated with this disorder.Here, we examine whether novel positive allosteric modulators (PAMs) selective for mGlu1 reverse electrophysiological effects and behavioral deficits in an MK‐801‐induced animal model of SCZ. We used ex vivo whole‐cell patch‐clamp electrophysiology to show that MK‐801 decreased the frequency of spontaneous inhibitory postsynaptic currents onto layer V pyramidal cells of the PFC, and this cortical disinhibition was reversed by mGlu1 activation. Furthermore, acute MK‐801 treatment induces inhibitory deficits onto PFC‐basolateral amygdala (BLA), but not PFC‐nucleus accumbens, projecting layer V pyramidal cells that can be reversed by selective mGlu1 activation. PFC‐BLA projections are known to contribute functionally to social‐approach behavior, while the BLA plays a critical role in object recognition and cognition broadly. We found that the mGlu1 PAM VU6004909 effectively reversed MK801‐induced deficits in social interaction and social novelty preference in a three‐chamber assay. Additionally, VU6004909 restored novel object recognition following MK‐801 treatment. In combination with our previous reports that mGlu1 PAMs reverse deficits in inhibitory transmission in the PFC, the current study provides strong evidence for mGlu1 PAMs as a promising novel approach for the treatment of social and cognitive deficits in SCZ patients.

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Indication	Highest Phase	Country/Location	Organization	Date
Nervous System Diseases	Preclinical	United States	Vanderbilt University	12 Dec 2024
Neurocognitive Disorders	Preclinical	United States	Vanderbilt University	12 Dec 2024

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