Melanin-concentrating hormone receptor: A therapeutic target for novel anxiolytics.

Anxiety disorders are chronic, disabling psychiatric disorders, and there is a growing medical need for the development of novel pharmacotherapeutic agents showing improved efficacy and an improved side effect profile as compared with the currently prescribed anxiolytic drugs. In the course of the search for next-generation anxiolytics, neuropeptide receptors have garnered interest as potential therapeutic targets, underscored by pivotal roles in modulating stress responses and findings from animal studies using pharmacological tools. Among these neuropeptide receptors, the type 1 receptor for melanin-concentrating hormone (MCH1), which has been demonstrated to be involved in an array of physiological processes, including the regulation of stress responses and affective states, has gained attraction as a therapeutic target for drugs used in the treatment of psychiatric disorders, including anxiety disorders. To date, a plethora of MCH1 antagonists have been synthesized, and studies using MCH1 antagonists and genetically manipulated mice lacking MCH1 have revealed that the blockade of MCH1 produces anxiolytic-like effects across diverse rodent paradigms. In addition, MCH1 antagonists have been demonstrated to show a rapid onset of antidepressant-like effects; therefore, they may be effective for conditions commonly encountered in patients with anxiety disorders, which is an advantage for anxiolytic drugs. Notably, MCH1 antagonists have not manifested the undesirable side effects observed with the currently prescribed anxiolytics. All these preclinical findings testify to the potential of MCH1 antagonists as novel anxiolytics. Although there are still issues that need to be resolved prior to the initiation of clinical trials, such as elucidating the precise neuronal mechanisms underlying their anxiolytic effects and exploring pertinent biomarkers that can be used in clinical trials, MCH1 blockade appears to be an attractive way to tackle anxiety disorders.

mGlu2/3 receptor antagonists for depression: overview of underlying mechanisms and clinical development.

Triggered by the ground-breaking finding that ketamine exerts robust and rapid-acting antidepressant effects in patients with treatment-resistant depression, glutamatergic systems have attracted attention as targets for the development of novel antidepressants. Among glutamatergic systems, group II metabotropic glutamate (mGlu) receptors, consisting of mGlu2 and mGlu3 receptors, are of interest because of their modulatory roles in glutamatergic transmission. Accumulating evidence has indicated that mGlu2/3 receptor antagonists have antidepressant-like effects in rodent models that mirror those of ketamine and that mGlu2/3 receptor antagonists also share underlying mechanisms with ketamine that are responsible for these antidepressant-like actions. Importantly, contrary to their antidepressant-like profile, preclinical studies have revealed that mGlu2/3 receptor antagonists are devoid of ketamine-like adverse effects, such as psychotomimetic-like behavior, abuse potential and neurotoxicity. Despite some discouraging results for an mGlu2/3 receptor antagonist decoglurant (classified as a negative allosteric modulator [NAM]) in patients with major depressive disorder, clinical trials of two mGlu2/3 receptor antagonists, a phase 2 trial of TS-161 (an orthosteric antagonist) and a phase 1 trial of DSP-3456 (a NAM), are presently on-going. mGlu2/3 receptors still hold promise for the development of safer and more efficacious antidepressants.

Antidepressants in the post-ketamine Era: Pharmacological approaches targeting the glutamatergic system.

The efficacy of currently available medications for depression is unsatisfactory, and that has spurred the development of novel antidepressants based on a hypothesis other than the monoamine hypothesis. Recent studies have revealed the importance of the glutamatergic system as a drug target for depression, and the validity of this hypothesis has been underpinned by the discovery of the antidepressant effects of ketamine, leading to the market launch of Spravato® nasal spray which delivers (S)-ketamine (esketamine). However, both ketamine and esketamine have unwanted adverse effects that hinder their routine use in daily practice. Extensive studies have elucidated the mechanisms underlying the antidepressant effects of ketamine, and that has encouraged numerous drug discovery activities to search for agents that retain a ketamine-like antidepressant profile but with lesser adverse effect liabilities. The discovery activities have included attempts to identify 1) the active substance(s) in the circulation after ketamine administration and 2) agents that act on the proposed mechanisms of action of ketamine. Clinical trials of agents discovered in the course of these activities are underway, and in 2022, AUVELITY™ (AXS-05; dextromethorphan with bupropion) was approved by the United States Food and Drug Administration. Drug development of post-ketamine agents should provide novel antidepressants that are safer, but as potent and rapidly acting as ketamine.

Evaluation of the Safety, Tolerability, and Pharmacokinetic Profiles of TP0473292 (TS-161), A Prodrug of a Novel Orthosteric mGlu2/3 Receptor Antagonist TP0178894, in Healthy Subjects and Its Antidepressant-Like Effects in Rodents.

BACKGROUND: TP0473292 (the active ingredient of TS-161) is a prodrug of a novel metabotropic glutamate (mGlu) 2/3 receptor antagonist being developed for the treatment of patients with depression. This study evaluated the safety, tolerability, and pharmacokinetics of orally administered TS-161 in healthy subjects. METHODS: This was a first-in-human, phase 1, randomized, double-blind, placebo-controlled, single-ascending dose (15-400 mg TS-161) and 10-day multiple-ascending dose (50-150 mg TS-161) study in healthy subjects, conducted from June 2019 through February 2020. Plasma and urine concentrations of the prodrug and its metabolites, and cerebrospinal fluid (CSF) concentrations of the active metabolite TP0178894 were measured to evaluate the pharmacokinetic profiles after oral administration of TS-161. RESULTS: Following single and multiple doses, TP0473292 was extensively converted into its active metabolite TP0178894. Plasma concentrations of TP0178894 reached peak (Cmax) within 5 hours post dose and declined with a t1/2 <13 hours. Plasma exposures of TP0178894 increased with increasing dose. TP0178894 penetrated into CSF and reached a Cmax of 9.892 ng/mL at a single dose of 100 mg, which was comparable with IC50 values of antagonist activity at mGlu2/3 receptors. The most frequently observed adverse events that showed exposure-related incidence during the study were nausea, vomiting, and dizziness. CONCLUSIONS: The mGlu2/3 receptor antagonist prodrug TP0473292 is safe and well-tolerated, is orally bioavailable in humans with extensive conversion into the active metabolite TP0178894 with sufficient CSF penetration to exert the anticipated pharmacological effects, and is a promising candidate for further clinical development in treatment of patients with depression.

Vasopressin V1B Receptor Antagonists as Potential Antidepressants.

Accumulating evidence shows that certain populations of depressed patients have impaired hypothalamus-pituitary-adrenal (HPA) axis function. Arginine-vasopressin (AVP) is one of the primary factors in HPA axis regulation under stress situations, and AVP and its receptor subtype (V1B receptor) play a pivotal role in HPA axis abnormalities observed in depression. Based on this hypothesis, several non-peptide V1B receptor antagonists have been synthesized, and the efficacies of some V1B receptor antagonists have been investigated in both animals and humans. V1B receptor antagonists exert antidepressant-like effects in several animal models at doses that attenuate the hyperactivity of the HPA axis, and some of their detailed mechanisms have been delineated. These results obtained in animal models were, at least partly, reproduced in clinical trials. At least 2 V1B receptor antagonists (TS-121 and ABT-436) showed tendencies to reduce the depression scores of patients with major depressive disorder at doses that attenuate HPA axis hyperactivity or block the pituitary V1B receptor. Importantly, TS-121 showed a clearer efficacy for patients with higher basal cortisol levels than for those with lower basal cortisol levels, which was consistent with the hypothesis that V1B receptor antagonists may be more effective for patients with HPA axis hyperactivity. Therefore, V1B receptor antagonists are promising approaches for the treatment of depression involving HPA axis impairment such as depression.

A Novel Potent and Selective Histamine H3 Receptor Antagonist Enerisant: In Vitro Profiles, In Vivo Receptor Occupancy, and Wake-Promoting and Procognitive Effects in Rodents.

Histamine H3 receptor antagonists/inverse agonists are known to enhance the activity of histaminergic neurons in the brain, thereby promoting arousal and cognition. Here, we report the in vitro and in vivo pharmacological profiles for a newly synthesized histamine H3 receptor antagonist/inverse agonist: [1-(4-{3-[(2R)-2-methylpyrrolidin-1-yl]propoxy}phenyl)-1H-pyrazol-4-yl](morpholin-4-yl)methanone monohydrochloride (enerisant hydrochloride). In vitro assays showed that enerisant was a competitive antagonist/inverse agonist with a high affinity and selectivity for human and rat histamine H3 receptors. Enerisant showed antagonist activity in vivo, as assessed using R-α-methylhistamine (a histamine H3 receptor agonist)-induced dipsogenia, and occupied the histamine H3 receptor in the frontal cortex in a dose-dependent manner. Enerisant also enhanced the extracellular levels of histamine in the posterior hypothalamus and the levels of dopamine and acetylcholine in the medial prefrontal cortex of rats. Enerisant exerted a procognitive effect or reversed scopolamine-induced cognitive impairment in a social recognition test and a novel object recognition test in rats at doses at which less than 50% of the histamine H3 receptor were occupied (0.03-0.3 mg/kg, p.o.). In contrast, higher doses (3-10 mg/kg, p.o.) at which nearly all the histamine H3 receptors were occupied were needed to exert wake-promoting effects in rats. These results indicate that enerisant is a potent and selective histamine H3 receptor antagonist/inverse agonist with the potential to promote arousal and procognition in rats. Moreover, the results also suggest that the histamine H3 receptor occupancy required to exert a pharmacological effect may vary depending on the domain that is being tested. SIGNIFICANCE STATEMENT: Enerisant is a novel histamine H3 receptor antagonist/inverse agonist that exerts wake-promoting and procognitive effects in addition to increasing the release of neurotransmitters related to these pharmacological effects in rodents. Moreover, an in vivo receptor binding study revealed that the in vivo occupancy of the histamine H3 receptor required to exert the pharmacological effects of enerisant varied, and such variations in required occupancy should be taken into account when performing dose selection in clinical studies.

Discovery of MGS0274, an ester prodrug of a metabotropic glutamate receptor 2/3 agonist with improved oral bioavailability.

We previously reported that MGS0008 is a selective group II metabotropic glutamate receptor (mGlu2/3 receptor) agonist that is effective in animal models of schizophrenia. MGS0008 is a highly hydrophilic glutamate analog and is therefore expected to show low oral bioavailability in humans. To improve the oral bioavailability of MGS0008, ester prodrugs of MGS0008 were synthesized and their usefulness was evaluated. Among the prodrugs, the l-menthol-ester prodrug 4h demonstrated preferable lipophilicity, good chemical stability, and a high conversion rate to MGS0008 in human and monkey liver microsomes. A pharmacokinetic study in monkeys revealed that the oral bioavailability of MGS0008 after oral dosing of compound 4h was approximately 15-fold higher than that after oral dosing of MGS0008. Based on these findings, a diastereomer of compound 4h (compound 4j, or MGS0274), was selected as a candidate for clinical drug development, and its besylate is currently under development for the treatment of schizophrenia (Development code: TS-134).

mGlu2/3 receptor as a novel target for rapid acting antidepressants.

Given that ketamine, a noncompetitive N-methyl-d-aspartate receptor antagonist that exerts rapid antidepressant effects in patients with treatment-resistant depression, also has undesirable adverse effects, agents that can be used as alternatives to ketamine have been actively pursued. Group II metabotropic glutamate (mGlu) receptors, consisting of mGlu2 and mGlu3 receptors, have emerged as one of the most promising targets in the development of ketamine-like antidepressants. Indeed, mGlu2/3 receptor antagonists have been demonstrated to exert rapid antidepressant effects in animal models and to be efficacious in animal models refractory to conventional antidepressants. Moreover, there are striking similarities between mGlu2/3 receptor antagonists and ketamine in terms of not only their antidepressant profiles, but also the underlying mechanisms of their antidepressant effects. Nonetheless, studies in rodents have shown that mGlu2/3 receptor antagonists do not cause ketamine-like adverse events, such as psychotomimetic-like behavior, abuse potential or neurotoxicity, supporting the usefulness of mGlu2/3 receptor antagonists as alternatives to ketamine. In this chapter, the past and recent research on the antidepressant effects of mGlu2/3 receptor antagonists will be reviewed. In particular, the potential of mGlu2/3 receptor antagonists as novel ketamine-like antidepressants will be emphasized.

Efficacy and safety of TS-121, a novel vasopressin V1B receptor antagonist, as adjunctive treatment for patients with major depressive disorder: A randomized, double-blind, placebo-controlled study.

Vasopressin 1B (V1B) receptor has a pivotal role in the regulation of the hypothalamus-adrenal-pituitary axis, and V1B receptor antagonists have shown efficacy in a number of preclinical models of depression. The efficacy and safety of, TS-121 (active ingredient: THY1773), a novel V1B receptor antagonist, was investigated in patients with major depressive disorder (MDD) who had an inadequate response to current antidepressant therapy. In a randomized, double-blind, placebo-controlled phase 2 study, 51 MDD patients (43 of whom completed the study) were randomly assigned to either TS-121 10 mg, 50 mg or placebo for 6 weeks treatment period. The primary endpoint was change from baseline on the Montgomery-Åsberg Depression Rating Scale (MADRS) score at week 6. The study was conducted from Jul 2017 to Dec 2018. The changes from baseline in MADRS score at week 6 (Least Square Mean [95% Confidence interval] were: TS-121 10 mg (-9.0 [-13.9, -4.1]), TS-121 50 mg (-9.0 [-13.4, -4.5]), and placebo (-6.4 [-10.7, -2.2]). TS-121 groups showed greater numerical reductions in MADRS score change from baseline compared to placebo, though these reductions did not achieve statistical significance. Similar trends of numerically greater improvements in TS-121 groups were observed across secondary endpoints. Higher baseline urinary and hair cortisol levels were associated with a greater separation between TS-121 groups and the placebo group in the primary endpoint. These findings, combined with favorable safety and tolerability, warrant further investigation of TS-121 in an adequately powered study in patients with MDD.

Medial PFC AMPA receptor and BDNF signaling are required for the rapid and sustained antidepressant-like effects of 5-HT1A receptor stimulation.

We previously reported that the serotonergic system is important for the antidepressant-like effects of ketamine, a non-competitive N-methyl-D-aspartate receptor antagonist, which produces rapid and long-lasting antidepressant effects in patients with major depressive disorder (MDD). In particular, selective stimulation of the 5-HT1A receptor in the medial prefrontal cortex (mPFC), as opposed to the somatic 5-HT1A autoreceptor, has been shown to play a critical role in the antidepressant-like actions of ketamine. However, the detailed mechanisms underlying mPFC 5-HT1A receptor-mediated antidepressant-like effects are not fully understood. Here we examined the involvement of the glutamate AMPA receptor and brain-derived neurotrophic factor (BDNF) in the antidepressant-like effects of 5-HT1A receptor activation in the mPFC. The results show that intra-mPFC infusion of the 5-HT1A receptor agonist 8-OH-DPAT induces rapid and long-lasting antidepressant-like effects in the forced swim, novelty-suppressed feeding, female urine sniffing, and chronic unpredictable stress tests. In addition, the results demonstrate that the antidepressant-like effects of intra-mPFC infusion of 8-OH-DPAT are blocked by co-infusion of an AMPA receptor antagonist or an anti-BDNF neutralizing antibody. In addition, mPFC infusion of 8-OH-DPAT increased the phosphorylation of signaling proteins downstream of BDNF, including mTOR, ERK, 4EBP1, and p70S6K. Finally, selective stimulation of the 5-HT1A receptor increased levels of synaptic proteins and synaptic function in the mPFC. Collectively, these results indicate that selective stimulation of 5-HT1A receptor in the mPFC exerts rapid and sustained antidepressant-like effects via activation of AMPA receptor/BDNF/mTOR signaling in mice, which subsequently increase synaptic function in the mPFC, and provide evidence for the 5-HT1A receptor as a target for the treatment of MDD.

Safety and pharmacokinetic profiles of MGS0274 besylate (TS-134), a novel metabotropic glutamate 2/3 receptor agonist prodrug, in healthy subjects.

AIMS: The safety and pharmacokinetics of single and multiple doses of a novel mGlu2/3 receptor agonist prodrug, MGS0274 besylate (TS-134), were investigated in healthy subjects. METHODS: Phase 1 single-ascending dose (5-20 mg) and multiple-ascending dose titration (5-80 mg) studies were conducted in healthy male and female subjects. Both studies were randomized, double-blinded and placebo-controlled. In one cohort of single-ascending dose study (10 mg), concentrations of MGS0008, the active compound, in the cerebrospinal fluid (CSF) were measured for up to 24 hours postdose. RESULTS: Following single and multiple oral administrations, MGS0274 was rapidly absorbed and extensively converted into MGS0008, which reached a maximum concentration (Cmax ) in plasma within 4 hours postdose and declined with a terminal half-life (t1/2 ) of around 10 hours. Plasma exposure to MGS0274 was minimal, accounting for approximately 3% of the area under the concentration-time curve (AUC) of MGS0008. Plasma Cmax and AUC of MGS0008 at steady state increased dose proportionally (5-80 mg). MGS0008 penetrated into CSF, with a CSF-to-plasma Cmax ratio of 3.66%, and was eliminated with a t1/2 of approximately 16 hours. The most frequent treatment-emergent adverse events observed following single and multiple oral administration included headache, nausea, somnolence, dizziness and vomiting. CONCLUSION: TS-134 is orally bioavailable in humans and converts rapidly and extensively to MGS0008, which exhibits good CSF penetration. Orally administered TS-134 was safe and generally well-tolerated; hence, TS-134 is a promising candidate for further clinical development for the treatment of disorders in which glutamatergic abnormalities are involved, such as schizophrenia.

mGlu2/3 receptor antagonists.

Abnormalities of glutamatergic transmission are implicated in neuropsychiatric disorders. Among the glutamate receptors, metabotropic (mGlu) 2/3 receptors have recently gained much attention as molecular targets for the treatment of several neuropsychiatric disorders including depression and anxiety. Both orthosteric and allosteric antagonists of mGlu2/3 receptors have been synthesized, and their therapeutic potential has been examined. These research activities have demonstrated the promise of mGlu2/3 receptor antagonists as potential treatment agents for the above-mentioned neuropsychiatric disorders. In particular, it has been considered that the antidepressant effects of mGlu2/3 receptor antagonists are worthy of pursuing, since the antidepressant profiles as well as synaptic/neural mechanisms involved in the actions of mGlu2/3 receptor antagonists are similar to those of ketamine, which has been demonstrated to show potent, rapid and sustained efficacy in patients with depression, even those resistant to the conventionally prescribed antidepressants. In this chapter, the general pharmacology of mGlu2/3 receptor antagonists and their therapeutic potential are reviewed. In particular, I focus on the usefulness of mGlu2/3 receptor antagonists as novel antidepressants, in comparison with ketamine.

Role of Serotonergic System in the Antidepressant Actions of mGlu2/3 Receptor Antagonists: Similarity to Ketamine.

Numerous studies have demonstrated the antidepressant effects of group II metabotropic glutamate (mGlu2/3) receptor antagonists in various rodent models. Importantly, it has been shown that the antidepressant effects of mGlu2/3 receptor antagonists in rodent models are similar to those of ketamine, which exerts rapid and long-lasting antidepressant effects in patients with major depressive disorders, including patients with treatment-resistant depression. In addition, the synaptic mechanisms underlying the effects of mGlu2/3 receptor antagonists are reported to be similar to those underlying the effects of ketamine. The roles of the serotonergic system in the antidepressant effects of mGlu2/3 receptor antagonists have recently been demonstrated. Moreover, it was investigated how mGlu2/3 receptor antagonists interact with the serotonergic system to exert antidepressant effects. Notably, the same neural mechanisms as those underlying the effects of ketamine may be involved in the antidepressant actions of the mGlu2/3 receptor antagonists. In this review, we shall summarize the antidepressant potential of mGlu2/3 receptor antagonists and their mechanisms of action in comparison with those of ketamine. In particular, we shall focus on the roles of the serotonergic system in the antidepressant actions of mGlu2/3 receptor antagonists.

Targeting of Metabotropic Glutamate Receptors for the Development of Novel Antidepressants.

Since discovering that ketamine has robust antidepressant effects, the glutamatergic system has been proposed as an attractive target for the development of novel antidepressants. Among the glutamatergic system, metabotropic glutamate (mGlu) receptors are of interest because mGlu receptors play modulatory roles in glutamatergic transmission, consequently, agents acting on mGlu receptors might not exert the adverse effects associated with ketamine. mGlu receptors have eight subtypes that are classified into three groups, and the roles of each mGlu receptor subtype in depression are being investigated. To date, the potential use of mGlu5 receptor antagonists and mGlu2/3 receptor antagonists as antidepressants has been actively investigated, and the mechanisms underlying these antidepressant effects are being delineated. Although the outcomes of clinical trials using an mGlu5 receptor negative allosteric modulator and an mGlu2/3 receptor negative allosteric modulator have not been encouraging, these trials have been inconclusive, and additional trials using other compounds with more appropriate profiles are needed. In contrast, the roles of group III mGlu receptors have not yet been fully elucidated because of a lack of suitable pharmacological tools. Nonetheless, investigations of the use of mGlu4 and mGlu7 receptors as drug targets for the development of antidepressants have been ongoing, and some interesting evidence has been obtained.

Is the History Repeated? Can (2R,6R)-Hydroxynorketamine be Another Antidepressant?

Historically, identification of active metabolites has contributed to drug discovery for psychiatric disorders. It has led to the identification of new medications such as desipramine (a metabolite of imipramine) and paliperidone (a metabolite of risperidone). (R,S)-Ketamine, which has been regarded as the greatest breakthrough in depression research, is rapidly and stereoselectively metabolized into a variety of metabolites. Therefore, identification of an active substance after administration of (R,S)-ketamine is a critical issue, not only to delineate the underlying mechanisms but also to pave the way to develop a new antidepressant. Recently, one of the metabolites of (R,S)-ketamine, namely, (2R,6R)-hydroxynorketamine (HNK) was proposed as an active metabolite formed after administration of (R,S)-ketamine, and even as being essential for (R,S)-ketamine to exert its antidepressant effects. However, this is still controversial. Indeed, we demonstrated that the antidepressant effect of (2R,6R)-HNK is not as potent as that of its parent compounds ((R)-ketamine and (R,S)-ketamine), and that (2R,6R)-HNK is not essential for (R)-ketamine to exert its antidepressant effects. From the historical point of view, however, there is potential to discover new medications by further investigations of (2R,6R)-HNK. Therefore, more careful and thorough investigation of (2R,6R)-HNK is needed for the discovery of more efficacious and safer antidepressants.

Lack of deuterium isotope effects in the antidepressant effects of (R)-ketamine in a chronic social defeat stress model.

RATIONALE: (R,S)-ketamine, an N-methyl-D-aspartate receptor (NMDAR) antagonist, exhibits rapid and long-lasting antidepressant effects and anti-suicidal ideation in treatment-resistant patients with depression. However, the precise mechanisms underlying the antidepressant actions of (R,S)-ketamine are unknown. Although the previous report demonstrated the deuterium isotope effects in the antidepressant actions of (R,S)-ketamine, the deuterium isotope effects in the antidepressant actions of (R)-ketamine, which is more potent than (S)-ketamine, are unknown. METHODS: We examined whether deuterium substitution at the C6 position could affect antidepressant effects of (R)-ketamine in a chronic social defeat stress (CSDS) model. RESULTS: Pharmacokinetic studies showed that levels of (2R,6R)-d1-hydroxynorketamine [(2R,6R)-d1-HNK], a final metabolite of (R)-d2-ketamine, in the plasma and brain after administration of (R)-d2-ketamine (10 mg/kg) were lower than those of (2R,6R)-HNK from (R)-ketamine (10 mg/kg), indicating deuterium isotope effects in the production of (2R,6R)-HNK. In contrast, levels of (R)-ketamine and its metabolite (R)-norketamine in the plasma and brain were the same for both compounds. In a CSDS model, both (R)-ketamine (10 mg/kg) and (R)-d2-ketamine (10 mg/kg) showed rapid and long-lasting (7 days) antidepressant effects, indicating no deuterium isotope effect in the antidepressant effects of (R)-ketamine. CONCLUSIONS: The present study suggests that deuterium substitution of hydrogen at the C6 position slows the metabolism from (R)-ketamine to (2R,6R)-HNK in mice. In contrast, we did not find the deuterium isotope effects in terms of the rapid and long-lasting antidepressant effects of (R)-ketamine in a CSDS model. Therefore, it is unlikely that (2R,6R)-HNK is essential for antidepressant effects of (R)-ketamine.