What mGluR2 modulators are in clinical trials currently?

Introduction to mGluR2

Definition and Role in the Central Nervous System
Metabotropic glutamate receptor 2 (mGluR2) is one of the eight members of the group of G-protein coupled receptors (GPCRs) that respond to the major excitatory neurotransmitter glutamate. Unlike ionotropic receptors that mediate fast synaptic transmission, mGluR2 is coupled to inhibitory Gi/Go proteins and modulates synaptic activity through longer-lasting, neuromodulatory effects. It is primarily located both pre- and perisynaptically, where it acts as an autoreceptor to decrease the release of glutamate and to help maintain synaptic homeostasis. The role of mGluR2 in the central nervous system (CNS) extends beyond simple neurotransmitter regulation; it is an integral component in processes such as attention, learning, working memory, and the regulation of neural network excitability. Its ability to modulate neurotransmission through allosteric mechanisms makes it an interesting target for disorders where glutamate hyperactivity is implicated.

Significance in Neurological Disorders
The overactivity of glutamatergic transmission has been associated with a range of neurological and psychiatric disorders including schizophrenia, anxiety, depression, epilepsy, and even neurodegenerative diseases. Excessive glutamate release or hypersensitivity of glutamate systems can lead to excitotoxicity—a process believed to contribute to neuronal injury and disease progression. As mGluR2 activation leads to an inhibitory effect on glutamate release, it represents a promising target for therapeutic intervention in disorders where glutamate imbalance is central to the pathophysiology. For instance, normalization of excessive glutamate signaling through mGluR2 modulators has been shown to reduce symptoms in animal models of schizophrenia and other CNS conditions, providing the rationale for advancing modulators into clinical trials.

In summary, mGluR2 is a receptor that plays a pivotal role in maintaining CNS excitability by modulating synaptic transmission, and its ability to do so positions it as a key target for disorders associated with glutamatergic dysregulation.

Current mGluR2 Modulators

Types of Modulators
mGluR2 modulators are a diverse group of small-molecule agents that can enhance or suppress receptor function through binding sites distinct from the primary, or “orthosteric,” glutamate-binding domain. They are predominantly categorized into two major types:

• Positive Allosteric Modulators (PAMs): PAMs bind to regulatory sites on the receptor and potentiate the effects of glutamate without activating the receptor directly. They enhance the receptor’s response only in the presence of the endogenous ligand, thus offering a mechanism for achieving receptor selectivity with limited side effects. Examples include compounds such as AZD8529, ADX71149 (also referred to as JNJ-40411813 in some literature), and JNJ-55375515, all of which have been developed with the aim of selectively enhancing mGluR2 signaling.

• Negative Allosteric Modulators (NAMs): Although less common in current clinical development, NAMs inhibit receptor activity by binding to non-orthosteric sites that reduce the receptor’s response to glutamate. They can be useful for conditions where downregulation of mGluR2 signaling might be beneficial. However, the current clinical focus has largely been on PAMs because potentiation of mGluR2 is seen as therapeutically favorable in conditions characterized by excessive glutamate levels.

Other classes that have been explored include orthosteric agonists, which bind directly at the glutamate site, though these typically lack the subtype selectivity that PAMs can achieve. This has made PAMs the preferred approach given their improved safety profiles and better specificity toward mGluR2, reducing potential off-target effects.

Mechanism of Action
Positive allosteric modulators (PAMs) of mGluR2 bind to allosteric (non-glutamate) sites on the receptor, most often located in the transmembrane domains. Their binding enhances the receptor's response to glutamate, effectively increasing the potency and/or efficacy of the endogenous ligand. This effect is highly state-dependent and imprint selective signaling properties that may mimic natural receptor regulation without the need for continuous receptor activation.

Because mGluR2 activation normally limits presynaptic glutamate release, PAMs amplify this homeostatic mechanism to restore balance in overactive glutamatergic circuits. In preclinical models, such modulation has been seen to improve cognitive deficits, reduce psychotic-like behaviors, and produce anti-epileptic effects, depending on the disease context. Unlike full agonists, PAMs are less likely to produce receptor desensitization, thereby supporting sustained therapeutic benefits over prolonged periods.

Thus, from a mechanistic perspective, mGluR2 PAMs operate by fine-tuning the receptor’s response to glutamate: they increase receptor sensitivity when glutamate is present, leading to reduced synaptic release of glutamate and ultimately normalization of overactive excitatory neurotransmission.

Clinical Trials of mGluR2 Modulators

Overview of Ongoing Clinical Trials
Currently, several mGluR2 modulators have entered clinical trials and are being studied for different indications. The clinical candidates include:

• AZD8529 – A positive allosteric modulator developed to target cognitive deficits and other symptoms in neuropsychiatric disorders such as schizophrenia. Multiple studies have been conducted in healthy subjects as well as in patient populations. Notably, there are clinical trials investigating the effects of AZD8529 on ketamine-induced working memory deficits and its efficacy and safety in adult schizophrenia patients. In addition, further studies assess multiple ascending doses in healthy subjects and even evaluate its potential in smoking cessation among female smokers.

• JNJ-55375515 – Another mGluR2 PAM that is currently under investigation in healthy subjects. Data from several studies, including a safety, tolerability, pharmacokinetics, and pharmacodynamics evaluation, indicate that JNJ-55375515 is being tested in healthy male subjects across multiple trial phases. Additionally, there is a trial registered under the WHO database which indicates further investigation into its safety profile and dosage escalation in healthy male subjects.

• ADX71149 (JNJ-40411813) – Marketed in some literature under this designation, ADX71149 is an mGluR2 positive allosteric modulator that has been explored primarily in the context of epilepsy. News reports and conference summaries highlight its promise in normalizing excessive glutamate release during seizures. A phase 2 proof-of-concept clinical study is being conducted to evaluate its efficacy in patients with epilepsy, with promising preclinical efficacy data published in peer-reviewed journals.

These candidates have been selected based on their favorable pharmacokinetic profiles and robust preclinical data that support their potential efficacy for various CNS disorders, especially those characterized by excessive glutamatergic neurotransmission.

Phase and Status of Trials
The clinical trials of the mGluR2 modulators are at various stages of development, reflecting the breadth of therapeutic applications being investigated:

• AZD8529 has been evaluated in multiple phases of clinical testing. There is a study that specifically examines its effects on ketamine-induced cortical stimulation and working memory-related activation in healthy volunteers—this trial was structured as a single-center, double-blind, randomized, crossover study. There have also been phase IIa studies looking at its efficacy, safety, tolerability, and pharmacokinetics in adult patients with schizophrenia. Besides, another phase I trial established the multiple ascending dose schedules in healthy subjects. Moreover, additional studies have looked at its effectiveness in smoking cessation among female populations, indicating an exploration of diverse therapeutic indications.

• JNJ-55375515 is undergoing clinical assessment primarily in healthy subjects. One reported phase (likely phase I given its design parameters focusing on safety, tolerability, and pharmacokinetics) recruited healthy male participants in a randomized, placebo-controlled, double-blind, single ascending dose study. A similar study has been conducted on healthy subjects with both single and multiple ascending doses to further assess the safety profile and PK parameters. Furthermore, another trial is registered under WHO, which confirms the progression of studies on JNJ-55375515 focusing on dose escalation and safety in healthy subjects.

• ADX71149 (JNJ-40411813) is being advanced into phase II clinical development, particularly in the area of epilepsy. According to news reports and recent conference summaries, ADX71149 is being evaluated as an adjunctive treatment for epilepsy. The trials aim to assess the efficacy, safety, tolerability, and pharmacokinetics in patients with refractory seizure conditions. Recent collaborative agreements indicate that the development of ADX71149 is being actively pursued, and clinical data suggest that this mGluR2 PAM is promising in mitigating seizure-related pathophysiology.

Each of these trials is designed to rigorously evaluate the benefits and safety profiles of these compounds. The phases indicate a progression from early (phase I) safety and pharmacokinetic evaluations in healthy volunteers to later-stage (phase IIa) trials that assess efficacy and dosing in targeted patient populations. The depth of investigation ensures that both the positive pharmacological effects and potential risk profiles are comprehensively understood.

Therapeutic Indications
The selection of therapeutic indications for mGluR2 modulators is driven by the receptor’s role in modulating glutamatergic neurotransmission and the diverse pathophysiology of CNS disorders. The current clinical trials reflect several indications:

• Schizophrenia and Cognitive Disorders:
AZD8529 has been evaluated in clinical trials for its potential to alleviate symptoms of schizophrenia, particularly cognitive impairments and negative symptoms. By enhancing mGluR2 activity, AZD8529 is hypothesized to normalize the glutamate transmission in brain regions implicated in schizophrenia, such as the prefrontal cortex. Its evaluation in crossover studies examining ketamine-induced impairments further supports this rationale. These studies suggest that potentiation of mGluR2 can counteract the excitatory imbalance thought to underlie some of the cognitive deficits in schizophrenia.

• Epilepsy:
ADX71149 (JNJ-40411813) is primarily being evaluated for its use in epilepsy. The therapeutic rationale is based on the receptor’s ability to reduce excessive glutamate release during seizure activity. Clinical trial reports suggest that by modulating mGluR2, ADX71149 could help restore glutamate balance and thereby mitigate seizure propagation and severity. The phase II study is expected to provide critical data on its efficacy as an adjunctive agent to conventional anti-epileptic drugs.

• Smoking Cessation:
Interestingly, some clinical trials have also investigated the role of mGluR2 modulators in smoking cessation. AZD8529, for instance, is currently being studied in a two-period crossover format in female smokers to evaluate its potential in reducing cravings and altering addictive behaviors. This indicates that mGluR2 signaling, through its general role in modulating neurotransmitter release, might have wider applications in addiction medicine.

• Potential Broad-Spectrum Applications in Neuropsychiatric Conditions:
While the primary indications in current clinical trials are schizophrenia and epilepsy, these modulators also hold promise for other conditions associated with glutamatergic dysregulation. Given the broad involvement of mGluR2 in modulating excitatory signals in the CNS, further clinical developments may explore its applications in anxiety disorders, depressive states, and possibly neurodegenerative diseases. The widespread interest in mGluR2 reflects its potential versatility as a therapeutic target.

In a general sense, mGluR2 modulators are being deployed in clinical trials with the aim not only to alleviate the symptoms of specific disorders, but also to modify the underlying neurochemical imbalances that contribute to the pathology of these diseases. This broad therapeutic potential is a significant motivating factor in the continued clinical development of these agents.

Challenges and Future Directions

Current Challenges in Development
Despite promising preclinical outcomes and encouraging results in early-phase clinical trials, several challenges remain in the development of mGluR2 modulators:

• Receptor Subtype Selectivity:
One of the primary challenges in developing mGluR2 modulators is achieving a high degree of selectivity over other glutamate receptor subtypes, particularly mGluR3. Early compounds often activate both mGluR2 and mGluR3, which can complicate the interpretation of clinical outcomes. Efforts are ongoing to refine chemical structures so that the modulators preferentially target mGluR2, thereby minimizing potential off-target effects.

• Pharmacokinetic and Pharmacodynamic Complexity:
Maintaining steady receptor modulation over prolonged periods without causing receptor desensitization is another concern. Clinical trials of compounds such as AZD8529 and JNJ-55375515 have extensively evaluated the pharmacokinetic properties to ensure that systemic exposure yields sufficient receptor engagement while avoiding rapid tolerance or adverse events. Optimizing absorption, distribution, and metabolism is key to long-term therapeutic efficacy.

• Clinical Efficacy vs. Safety Profile:
Achieving robust clinical efficacy, particularly in complex disorders like schizophrenia and epilepsy, is challenging; the clinical trial data need to demonstrate not only symptomatic improvement but also a meaningful change in disease progression. In phase II trials, endpoints such as changes in working memory, reductions in seizure frequency, or improvement in quality of life are measured. However, modest effects or subtle signals of efficacy can be difficult to interpret against a background of placebo response and intersubject variability.

• Complexity of CNS Disorders:
Neurological and psychiatric disorders are multifactorial and often involve multiple dysregulated pathways. While mGluR2 potentiation targets a key mechanism in glutamate neurotransmission, it is one of many factors contributing to disease pathology. Designing clinical trials that can account for the heterogeneity in symptom presentation and disease progression remains a significant difficulty, and will likely require the integration of biomarker studies and patient stratification strategies.

Future Prospects and Research Directions
Looking ahead, several trends and research directions appear promising for the future development of mGluR2 modulators:

• Improved Molecular Design:
Advances in medicinal chemistry and structure-based drug design are expected to yield new compounds with enhanced selectivity and improved pharmacokinetic profiles. The ongoing work to fine-tune the allosteric binding sites has already led to compounds like AZD8529 and JNJ-55375515, and further iterations may resolve the long-standing issues of receptor selectivity and sustained efficacy.

• Combination Therapies and Precision Medicine Approaches:
In the context of complex CNS disorders, combination therapies that target multiple pathways may provide enhanced efficacy. mGluR2 modulators might eventually be used in combination with existing antipsychotics, anti-epileptics, or other neuromodulators to achieve better clinical outcomes. Precision medicine approaches or the use of biomarkers to stratify patient populations could further refine the therapeutic potential of these agents.

• Expansion into New Indications:
Beyond schizophrenia and epilepsy, other neuropsychiatric and neurodegenerative conditions characterized by glutamatergic imbalance, such as anxiety disorders, depression, and even Alzheimer’s disease, could benefit from mGluR2 modulators. Given the receptor’s role in dampening excitatory neurotransmission, future clinical trials might explore these agents in a broader range of disorders.

• Long-term Safety and Efficacy Trials:
The next generation of studies will likely involve long-term trials that assess not only the immediate effects of mGluR2 modulation but also the long-term benefits in terms of neuroprotection and symptom modification. These trials will be crucial in understanding both the therapeutic windows and the potential for tolerance or receptor downregulation over time.

• Integration with Neuroimaging and Functional Assays:
The future direction of research also includes integrating functional imaging studies and neurophysiological assessments to provide real-time evidence of receptor engagement and synaptic changes following treatment with mGluR2 modulators. Such approaches will help bridge the gap between molecular pharmacology and clinical outcomes, further informing drug development decisions.

In summary, while current clinical trials of mGluR2 modulators reflect significant progress in addressing glutamatergic dysregulation, ongoing efforts to refine chemical profiles, improve trial designs, and explore new patient populations will help further define their place in the therapeutic landscape.

Conclusion
In conclusion, mGluR2 modulators represent a highly promising class of therapeutic agents with the potential to address several neurological disorders characterized by an imbalance in glutamate neurotransmission. The current pipeline includes several leading compounds such as AZD8529, JNJ-55375515, and ADX71149, all of which are being evaluated in various clinical trial phases and in distinct patient populations. AZD8529, for example, has been studied in healthy volunteers and schizophrenia patients—ranging from phase I studies assessing working memory impairments induced by ketamine to phase IIa trials in adult schizophrenia patients and even expanded to smoking cessation paradigms. JNJ-55375515, another mGluR2 PAM, is undergoing rigorous safety and pharmacokinetic evaluation in healthy subjects, with multiple studies supporting its early-stage development. ADX71149, which is aligned with the mGluR2 mechanism and is being explored for refractory epilepsy, further highlights the growing clinical interest in modulating excitatory glutamate release in disease states.

From a general perspective, mGluR2 modulation through allosteric potentiation offers the advantage of enhancing endogenous glutamate’s regulatory effects without overactivating the receptor, thereby minimizing side effects. Specifically, the detailed preclinical data, coupled with carefully designed clinical trials, underscore the promise of these agents in not only mitigating symptoms but also potentially modifying disease progression in disorders such as schizophrenia and epilepsy.

However, the development of these modulators is not without challenges; issues such as receptor subtype selectivity, the variability of CNS disorders, and optimized pharmacokinetic profiles still require further research. Future directions include improved molecular designs, exploring combination therapies, longer-term safety and efficacy studies, and the integration of advanced neuroimaging techniques to better correlate molecular effects with clinical outcomes.

Ultimately, the current clinical trials are a testament to the significant progress made in this field, and with continued research and iterative drug development, mGluR2 modulators are poised to make important contributions to the treatment of a broad range of neurological disorders. The overarching goal remains to leverage the unique capacity of mGluR2 PAMs to normalize glutamatergic signaling—a pursuit that offers hope for more effective, targeted, and personalized treatments in the near future.