What GPR38 agonists are in clinical trials currently?

Introduction to GPR38

Definition and Biological Role

GPR38 is classified among the orphan GPCRs—members of a large receptor family for which the endogenous activating ligand(s) has not yet been firmly established. Orphan receptors like GPR38 are typified by having dispersed tissue expression and often remain underexplored in comparison with their better characterized counterparts such as GPR35 or GPR40. In many cases, orphan GPCRs offer an enticing opportunity to uncover new mechanisms for disease modulation because their roles under physiologic conditions have typically remained elusive. Although detailed functional annotations are sparse when compared to more validated targets, emerging research indicates that GPR38 is expressed in select tissues and may play a role in modulating intracellular signaling cascades that could impact physiological responses such as immune function, neural signaling, or metabolic control. Many orphan receptors have been the subject of recent drug discovery projects because validation efforts—even before deorphanization—can reveal untapped therapeutic potential.

Relevance in Therapeutics

Therapeutically, orphan GPCRs are viewed as promising targets because they may open new avenues for treating disease states that have not been addressed by conventional targets. For example, receptors like GPR35 and GPR88 have been linked with inflammatory conditions, metabolic disorders, and neurological diseases. By analogy, although the specific role of GPR38 is not yet fully elucidated, basic research suggests that establishing its functional role might uncover new pathways to modulate patient outcomes in diseases with an unmet medical need. In many drug discovery programs, the identification of a receptor’s endogenous ligand or the discovery of potent synthetic agonists/antagonists catalyzes translational efforts. Because of this, GPR38 is cited as a potential candidate for future therapeutic intervention. However, to date, the level of translational maturity for GPR38 lags behind that of other orphan receptors that have already entered clinical development.

GPR38 Agonists

Known Agonists and Their Mechanism of Action

In the emerging landscape of orphan GPCR research, developing small molecule agonists serves two main purposes. First, these agonists can function as molecular probes that allow researchers to delineate the receptor’s downstream signaling pathways. Second, they offer the possibility of translating preclinical findings into therapeutic candidates that could ultimately modulate target-mediated disease processes. For more established targets like GPR35, synthetic agonists have been optimized to achieve nanomolar potency and cross-species efficacy. In contrast, for GPR38, the published literature and data in the Synapse database do not yet describe any well‐characterized, potent, and selective synthetic agonists that have been advanced to the point of clinical evaluation. In preclinical research settings, medicinal chemists may sometimes generate early “tool” molecules that help interrogate receptor physiology; however, none of the available Synapse sources provide data or reference numbers indicating that such molecules for GPR38 are undergoing formal clinical investigation. Mechanistically, agonists of comparable orphan GPCRs typically initiate conformational changes that lead to downstream activation of G protein–mediated second messenger cascades (e.g., changes in cAMP, intracellular Ca²⁺ release, or MAPK activation). Although it is plausible that similar pathways may be induced by putative GPR38 agonists, specific studies demonstrating such effects for GPR38 remain either unpublished or in the early stages of preclinical exploration. Thus, the mechanism of action for potential GPR38 agonists remains prospective rather than established.

Therapeutic Areas of Interest

It is common for orphan GPCR agonists, when eventually characterized and validated, to target several therapeutic areas. For example, other orphan receptors such as GPR35 have been linked to inflammatory bowel disease and cardiovascular indications, while GPR40 agonists are under evaluation for type 2 diabetes due to their ability to enhance glucose-stimulated insulin secretion. Extrapolating from these examples, one could expect that GPR38 may also be explored in conditions where modulation of cellular signaling is critical. Potential areas of interest for GPR38 therapeutics might include metabolic disorders, neuroinflammation, pain management, or even cancer if underlying signaling alterations warrant such an approach. However, without clear deorphanization and pharmacological characterization, the precise disease areas remain speculative. Preclinical research could eventually point to specific translational opportunities if GPR38-regulated pathways are found to be perturbed in a particular disease setting. At the current time, the therapeutic relevance of GPR38 remains an open question that is yet to be addressed in detail by the Synapse research database or by corresponding preclinical and clinical publications.

Clinical Trials of GPR38 Agonists

Overview of Current Trials

A comprehensive review of the provided Synapse references reveals a number of clinical trials covering different GPCR targets. For instance, multiple clinical studies exist for motilin receptor agonists (GSK962040) and a range of studies are also enumerated for other receptors such as GPR35 and GPR40. However, when specifically searching for GPR38, the Synapse clinical trial registry and related news sources do not yield any listings that indicate active clinical investigations for GPR38 agonists. Unlike other GPCR targets that have been deorphanized and for which synthetic agonists have been generated and advanced into clinical development, no evidence currently exists in the Synapse data regarding GPR38-specific trials. This absence of data suggests that any candidate molecules that might act as GPR38 agonists are either still in the discovery or early preclinical phases or are yet to be identified as promising candidates to enter clinical development.

Phases and Objectives

In clinical research programs, the progression from preclinical identification to early-phase studies typically follows a clear pattern. For well-established GPCR targets, Phase I trials are designed to assess safety, tolerability, pharmacokinetics, and pharmacodynamics using healthy volunteers. Phase II studies then expand into patient populations to evaluate efficacy and further safety profiles. Reviewing the clinical trial descriptions provided for motilin receptor agonists and others, one notes that the endpoints measured include metrics such as gastric emptying rates, pharmacodynamic markers of receptor activation, and therapeutic efficacy in specific diseases. In contrast, because GPR38 agonists are not registered in any current phase – neither Phase I nor in later phases – there is no specific objective or study design available in the Synapse dataset for a clinical program in this area. Consequently, research on GPR38 remains confined to early discovery activities, and subsequent research pipelines will be required to validate any initial hits and propel them toward early clinical trials. As no candidate molecules have met the criteria for clinical investigation, the objectives that would accompany such trials—such as dose escalation, safety evaluation, receptor occupancy assessments, and early efficacy signals—are not documented for GPR38 agonists.

Challenges and Future Prospects

Current Challenges in Development

The challenges in advancing GPR38 agonists into clinical trials can stem from several factors that are common to orphan GPCR research. First, because endogenous ligands for orphan receptors are often not definitively identified, there is a lack of clarity surrounding receptor physiology and the best strategies for modulating receptor activity. In some cases, the identification of high-affinity, selective synthetic agonists is complicated by issues of species selectivity; this is well documented in the GPR35 literature, for example, where compounds show variability in potency between human and rodent receptors. A similar problem might be encountered for GPR38 if ligands active at the human receptor do not translate well into preclinical species models. Second, as with many GPCR drug discovery projects, medicinal chemistry efforts for GPR38 agonists must optimize both potency and pharmacokinetic properties. The track record from other GPCR targets indicates that once a promising molecule is discovered, extensive structure–activity relationship (SAR) studies are required. For instance, optimization efforts with GPR40 agonists like AM-1638 and related compounds have revealed challenges in achieving full agonism versus partial agonism, as well as issues with receptor binding kinetics and complementarity to G protein signaling domains. The same hurdles can be expected for GPR38, but available Synapse data does not yet document any such optimized series for this receptor. Third, a significant challenge is the limited translational information available regarding receptor function. In the absence of a well-established biological role or clear pathophysiological association, deciding upon the appropriate clinical endpoints becomes uncertain. Many orphan receptors suffer from this gap in knowledge, and GPR38 is no exception. Without a defined role in disease pathology, pharmaceutical companies may be hesitant to invest in the necessary long-term research and development required to translate early preclinical findings into human studies. Finally, safety profiles for agonists at orphan receptors might be unpredictable, and adverse off-target effects may be discovered late in the development process. This situation has been encountered with other targets such as GPR40 agonists (e.g., TAK-875), where hepatotoxicity halted clinical progress. Such intrinsic risks add an extra layer of challenge in validating compounds to proceed into human trials.

Future Research Directions

Future directions for GPR38 research will require tackling both the biological and chemical challenges outlined above. First, deorphanization efforts remain a priority. Advanced techniques such as high-throughput screening, use of label-free detection methods, and structure-guided drug design can help identify candidate molecules that modulate GPR38 activity. Researchers may also utilize homology modeling and mutagenesis—as demonstrated for other orphan GPCRs—to identify key residues in the binding pocket that can be exploited for agonist development. Second, once potential agonist chemotypes are identified in vitro, extensive preclinical validation will be necessary. This includes demonstrating that these molecules can activate GPR38 in cellular assays and establishing the downstream signaling cascades that mediate physiological effects. Mechanistic studies could focus on whether GPR38 activation leads to changes in second messengers, such as cAMP, intracellular calcium, or ERK pathway activation. These experiments would provide the necessary proof of concept to justify advancing a candidate molecule to in vivo studies. Third, the process of lead optimization should emphasize achieving quantitative balance between potency, receptor selectivity, and desired ADME (absorption, distribution, metabolism, and excretion) profiles. Lessons from other GPCR programs, such as those for GPR40 and GPR35, can be instructive here. Emphasis should also be placed on minimizing the risk of species differences that commonly complicate extrapolation from animal models to humans. Developing compounds that demonstrate similar potencies in both rodent models and human cell lines could help smooth the transition into clinical trials. Furthermore, researchers may explore dual-target strategies or allosteric modulation of GPR38 to enhance therapeutic outcomes. In several cases, partial agonism or the combination of receptor targeting with other complementary mechanisms has yielded improved efficacy and safety profiles. Even though such approaches are not yet documented for GPR38, they remain an interesting avenue for future research. Finally, defining relevant therapeutic indications for GPR38 will be crucial. Preclinical studies should aim to correlate receptor expression and function with disease models. This may involve using genomic, proteomic, and metabolomic analyses to understand the role of GPR38 in disease pathology. Once a link is established—such as in metabolic dysregulation, neurodegenerative disorders, or inflammatory conditions—clinical endpoints can be devised to show early proof of efficacy in human subjects. Engaging in early dialogue with regulatory bodies based on robust preclinical data may also facilitate a smoother transition into early-phase clinical trials when candidate molecules are ready for human evaluation.

Conclusion

In summary, a comprehensive review of the available Synapse material shows that there are currently no GPR38 agonists in clinical trials. Despite significant progress with other GPCR targets (including motilin receptor agonists, GPR35 agonists, and GPR40 agonists) as documented within the Synapse database, the research and clinical development of GPR38 agonists remain in very early preclinical stages or might not have been initiated yet. This review began with an overview of GPR38 as an orphan receptor whose definition and biological role have only recently garnered attention. While orphan GPCRs such as GPR38 hold enormous therapeutic promise due to their unique signaling properties and potential involvement in unaddressed disease pathways, the absence of well-defined endogenous ligands and comprehensive functional studies has limited the discovery of potent agonists that could be safely advanced into human clinical trials. Next, under the GPR38 agonists section, we discussed that although analogous receptor targets have benefited from state-of-the-art drug discovery platforms to generate potent synthetic agonists with well-characterized mechanisms of action, GPR38 remains underexplored. No specific candidate compounds with robust preclinical validation for GPR38 have been highlighted in the Synapse sources. Consequently, there are also no associated therapeutic areas of interest that have been fully delineated for clinical trial entry. When examining the clinical trials of GPR38 agonists, it is clear that Synapse references document several trials for other GPCR agonists—ranging from first‐time‐in‐human dose-escalation studies to proof-of-concept trials—but noticeably absent are any entries related to GPR38. This means that from a clinical perspective, the current pipeline for GPR38 agonists is empty. The objectives, endpoints, phases, and safety and dosing guidelines typical of GPCR clinical trials are not available for GPR38 because no candidate has yet advanced that far. The challenges in developing GPR38 agonists are multifaceted. They include the inherent difficulties of deorphanization, optimization issues arising from potential species selectivity, and the uncertain translation of in vitro potency to in vivo efficacy. In addition, the absence of clear disease indications compounded by potential safety liabilities further hinders the progression of any early identified GPR38 modulators into clinical trials. These challenges require a coordinated effort that leverages both chemical biology and clinical research insights. Moving forward, future research directions should concentrate on robust identification and characterization of potential GPR38 modulators. Structure-guided drug design, coupled with innovative pharmacological screening methods, is necessary to generate high-affinity agonists with acceptable drug-like properties. Once promising candidates are identified, rigorous preclinical studies must establish proof of mechanism and therapeutic relevance in relevant animal models before any early-phase human trials can be contemplated. In doing so, lessons learned from other orphan GPCR programs will be invaluable, offering paradigms that might be adapted to the particular challenges of modulating GPR38. Moreover, ultimately defining the pathological role of GPR38 in disease will be critical for justifying the investment required to move such an agonist into clinical development. In conclusion, the current absence of clinical trials for GPR38 agonists indicates that the field remains in the discovery phase. For stakeholders and researchers, this represents both a challenge and an opportunity. By bridging the knowledge gap concerning GPR38 signaling and function through focused preclinical efforts, the scientific community can pave the way for future clinical development endeavors. Progress in this area will require sustained investment, collaborative efforts, and innovative research strategies. As the understanding of GPR38 evolves over time, it is expected that suitable candidate molecules may eventually emerge, leading to potential clinical trials that will explore their efficacy and safety in human disease contexts. Until then, it is clear from the available Synapse material that no GPR38 agonists are in clinical trial development at present.