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The N-methyl-d-aspartate receptor antagonist, ketamine, exhibits rapid and sustained antidepressant activity in patients with treatment-resistant depression (TRD), but its use is associated with psychotomimetic side effects. Evidence has suggested that the activation of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors followed by activation of the mechanistic target of rapamycin (mTOR) signaling pathway and production of brain derived neurotrophic factor (BDNF) protein may underlie the antidepressant efficacy of ketamine. In this study, we characterized the antidepressant-like effects of TAK-653, a novel AMPA receptor potentiator with virtually no agonistic activity. In rat primary cortical neurons, TAK-653 significantly increased phosphorylated and activated forms of mTOR and p70S6 kinase and their upstream regulators Akt and extracellular signal-regulated kinase (ERK). TAK-653 also significantly increased BDNF protein levels in rat primary cortical neurons. Ketamine at 30 mg/kg, i.p. produced antidepressant-like effects in the reduction of submissive behavior model (RSBM) in rats. Ketamine's antidepressant-like effect was blocked by pretreatment with the AMPA receptor antagonist NBQX at 10 mg/kg, i.p., indicating the essential role of AMPA receptor activation in the antidepressant-like effect of ketamine. Consistent with this finding, a sub-chronic administration of TAK-653 for 6 days produced significant antidepressant-like effect in the rat RSBM. Unlike ketamine, however, TAK-653 did not induce a hyperlocomotor response in rats, which is a behavioral index associated with psychotomimetic side effects in humans. TAK-653 may be a promising drug for the treatment of major depressive disorders including TRD with the potential for an improved safety profile compared with ketamine., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Huntington's disease (HD) is an inherited neurodegenerative disorder caused by a CAG repeat expansion in the huntingtin gene ( HTT ). Disease progression is characterized by the loss of vulnerable neuronal populations within the striatum. A consistent phenotype across HD models is disruption of nucleocytoplasmic transport and nuclear pore complex (NPC) function. Here we demonstrate that high content imaging is a suitable method for detecting mislocalization of lamin-B1, RAN and RANGAP1 in striatal neuronal cultures thus allowing a robust, unbiased, highly powered approach to assay nuclear pore deficits. Furthermore, nuclear pore deficits extended to the selectively vulnerable DARPP32 + subpopulation neurons, but not to astrocytes. Striatal neuron cultures are further affected by changes in gene and protein expression of RAN, RANGAP1 and lamin-B1. Lowering total HTT using HTT- targeted anti-sense oligonucleotides partially restored gene expression, as well as subtly reducing mislocalization of proteins involved in nucleocytoplasmic transport. This suggests that mislocalization of RAN, RANGAP1 and lamin-B1 cannot be normalized by simply reducing expression of CAG-expanded HTT in the absence of healthy HTT protein., Competing Interests: YU and AK were employed by the company Takeda Pharmaceutical Company Limited. This study received funding from Takeda Pharmaceuticals Ltd. The funder was involved in the study design. This study received funding from Cerevance, Inc. Cerevance, Inc., was not involved in the study design, collection, analysis, interpretation of data, the writing of this article, or the decision to submit it for publication. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Lange, Wood-Kaczmar, Ali, Farag, Ghosh, Parker, Casey, Uno, Kunugi, Ferretti, Andre and Tabrizi.)

Agonistic profiles of AMPA receptor (AMPA-R) potentiators may be associated with seizure risk and bell-shaped dose-response effects. Here, we report the pharmacological characteristics of a novel AMPA-R potentiator, TAK-653, which exhibits minimal agonistic properties. TAK-653 bound to the ligand binding domain of recombinant AMPA-R in a glutamate-dependent manner. TAK-653 strictly potentiated a glutamate-induced Ca 2+ influx in hGluA1i-expressing CHO cells through structural interference at Ser743 in GluA1. In primary neurons, TAK-653 augmented AMPA-induced Ca 2+ influx and AMPA-elicited currents via physiological AMPA-R with little agonistic effects. Interestingly, TAK-653 enhanced electrically evoked AMPA-R-mediated EPSPs more potently than AMPA (agonist) or LY451646 (AMPA-R potentiator with a prominent agonistic effect) in brain slices. Moreover, TAK-653 improved cognition for both working memory and recognition memory, while LY451646 did so only for recognition memory, and AMPA did not improve either. These data suggest that the facilitation of phasic AMPA-R activation by physiologically-released glutamate is the key to enhancing synaptic and cognitive functions, and nonselective activation of resting AMPA-Rs may negatively affect this process. Importantly, TAK-653 had a wide safety margin against convulsion; TAK-653 showed a 419-fold (plasma C max ) and 1017-fold (AUC plasma ) margin in rats. These findings provide insight into a therapeutically important aspect of AMPA-R potentiation., (© 2021. The Author(s).)

We have recently discovered an alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPA-R) potentiator TAK-137, 9-(4-phenoxyphenyl)-3,4-dihydropyrido[2,1-c][1,2,4] thiadiazine 2,2-dioxide with little agonistic effect. Under preclinical evaluation, TAK-137 demonstrated potent pro-cognitive effects with lower risks of seizure and bell-shaped dose response than LY451646, a potent AMPA-R potentiator, in rodents and monkeys. In this study, using rat primary cultured hippocampal neurons we explored the electrophysiological characterization of TAK-137 on native AMPA-Rs. TAK-137 dose-dependently enhanced AMPA-induced inward currents; its potency in the presence of AMPA was comparable to that of LY451646. The inward currents enhanced by TAK-137 were almost completely inhibited by GYKI53655, a selective AMPA-R blocker. Moreover, TAK-137 did not affect N-methyl- D -aspartate (NMDA)-activated inward currents, which suggests the AMPA-R-selective activation by TAK-137. In the absence of AMPA-R agonist, LY451646 at 30 μM induced slowly developing large inward currents, whereas TAK-137 at 30 μM exhibited a slight impact on baseline holding currents, further supporting the lower agonistic properties of TAK-137 than LY451646. Similar to LY451646, TAK-137 also increased the potency and binding affinity of AMPA for AMPA-Rs. These results indicate that TAK-137 is a highly potent and selective potentiator with little agonistic effect against native AMPA-Rs. Much greater agonistic effects of LY451646 than of TAK-137 may contribute to the increased risks of seizure and bell-shaped dose response in vivo., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Ketamine produces a rapid-onset antidepressant effect in patients with treatment-resistant depression (TRD), although it concurrently causes undesirable psychotomimetic side effects. Accumulating evidence suggests that ketamine produces antidepressant effects via activation of the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPA-R), with consequent activation of the mammalian target of rapamycin (mTOR) pathway and up-regulation of brain-derived neurotrophic factor (BDNF). We previously reported that TAK-137, an AMPA-R potentiator with little agonistic effect, had potent procognitive effects with lower risks of bell-shaped dose-response and seizure induction. In this study, we characterized the potential of TAK-137 as a novel antidepressant in rats. In rat primary cortical neurons, TAK-137 increased the phosphorylated form of Akt, extracellular signal-regulated kinase, mTOR, and p70S6 kinase, and dose-dependently increased the expression level of BDNF protein. The antidepressant-like effects of ketamine and TAK-137 were assessed on the day after final administration using the novelty-suppressed feeding test in rats. A single intraperitoneal administration of ketamine shortened the latency to feed. Under these conditions, oral administration of TAK-137 for 3 days shortened the feeding latency. Ketamine induced hyperlocomotion and reduced prepulse inhibition, which may be associated with psychotomimetic effects, while TAK-137 did not. TAK-137 may be a safer and rapid-onset therapeutic drug for the treatment of major depressive disorder, including TRD., (Copyright © 2019 Elsevier Inc. All rights reserved.)

The downregulation of the glutamate system may be involved in positive, negative, and cognitive symptoms of schizophrenia. Through enhanced glutamate signaling, the activation of the α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA) receptor, an ionotropic glutamate receptor, could be a new therapeutic strategy for schizophrenia. TAK-137 is a novel AMPA receptor potentiator with minimal agonistic activity; in this study, we used rodents and nonhuman primates to assess its potential as a drug for schizophrenia. At 10 mg kg -1 p.o., TAK-137 partially inhibited methamphetamine-induced hyperlocomotion in rats, and at 3, 10, and 30 mg kg -1 p.o., TAK-137 partially inhibited MK-801-induced hyperlocomotion in mice, suggesting weak effects on the positive symptoms of schizophrenia. At 0.1 and 0.3 mg kg -1 p.o., TAK-137 significantly ameliorated MK-801-induced deficits in the social interaction of rats, demonstrating potential improvement of impaired social functioning, which is a negative symptom of schizophrenia. The effects of TAK-137 were evaluated on multiple cognitive domains-attention, working memory, and cognitive flexibility. TAK-137 enhanced attention in the five-choice serial reaction time task in rats at 0.2 mg kg -1 p.o., and improved working memory both in rats and monkeys: 0.2 and 0.6 mg kg -1 p.o. ameliorated MK-801-induced deficits in the radial arm maze test in rats, and 0.1 mg kg -1 p.o. improved the performance of ketamine-treated monkeys in the delayed matching-to-sample task. At 0.1 and 1 mg kg -1 p.o., TAK-137 improved the cognitive flexibility of subchronic phencyclidine-treated rats in the reversal learning test. Thus, TAK-137-type AMPA receptor potentiators with low intrinsic activity may offer new therapies for schizophrenia.

Activation of α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid receptor (AMPA-R) is a promising strategy to treat psychiatric and neurological diseases if issues of bell-shaped response and narrow safety margin against seizure can be overcome. Here, we show that structural interference at Ser743 in AMPA-R is a key to lower the agonistic effect of AMPA-R potentiators containing dihydropyridothiadiazine 2,2-dioxides skeleton. With this structural insight, TAK-137, 9-(4-phenoxyphenyl)-3,4-dihydropyrido[2,1-c][1,2,4]thiadiazine 2,2-dioxide, was discovered as a novel AMPA-R potentiator with a lower agonistic effect than an AMPA-R potentiator LY451646 ((R)-N-(2-(4'-cyanobiphenyl-4-yl)propyl)propane-2-sulfonamide) in rat primary neurons. TAK-137 induced brain-derived neurotrophic factor in neurons in rodents and potently improved cognition in both rats and monkeys. Compared to LY451646, TAK-137 had a wider safety margin against seizure in rats. TAK-137 enhanced neural progenitor proliferation over a broader range of doses in rodents. Thus, TAK-137 is a promising AMPA-R potentiator with potent procognitive effects and lower risks of bell-shaped response and seizure. These data may open the door for the development of AMPA-R potentiators as therapeutic drugs for psychiatric and neurological diseases.

α -Amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA) receptor (AMPA-R) potentiators with brain-derived neurotrophic factor (BDNF)-induction potential could be promising as therapeutic drugs for neuropsychiatric and neurologic disorders. However, AMPA-R potentiators such as LY451646 have risks of narrow bell-shaped responses in pharmacological effects, including in vivo BDNF induction. Interestingly, LY451646 and LY451395, other AMPA-R potentiators, showed agonistic effects and exhibited bell-shaped responses in the BDNF production in primary neurons. We hypothesized that the agonistic property is related to the bell-shaped response and endeavored to discover novel AMPA-R potentiators with lower agonistic effects. LY451395 showed an agonistic effect in primary neurons, but not in a cell line expressing AMPA-Rs, in Ca 2+ influx assays; thus, we used a Ca 2+ influx assay in primary neurons and, from a chemical library, discovered two AMPA-R potentiators with lower agonistic effects: 2-(((5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetyl)amino)-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxamide (HBT1) and (3S)-1-(4-tert-butylphenyl)-N-((1R)-2-(dimethylamino)-1-phenylethyl)-3-isobutyl-2-oxopyrrolidine-3-carboxamide (OXP1). In a patch-clamp study using primary neurons, HBT1 showed little agonistic effect, whereas both LY451395 and OXP1 showed remarkable agonistic effects. HBT1, but not OXP1, did not show remarkable bell-shaped response in BDNF production in primary neurons. HBT1 bound to the ligand-binding domain (LBD) of AMPA-R in a glutamate-dependent manner. The mode of HBT1 and LY451395 binding to a pocket in the LBD of AMPA-R differed: HBT1, but not LY451395, formed hydrogen bonds with S518 in the LBD. OXP1 may bind to a cryptic binding pocket on AMPA-R. Lower agonistic profile of HBT1 may associate with its lower risks of bell-shaped responses in BDNF production in primary neurons., (Copyright © 2018 by The American Society for Pharmacology and Experimental Therapeutics.)

In cultured astrocytes, PACAP activates extracellular signal-regulated kinase (ERK) and induces cell proliferation at picomolar concentrations. Here, we examined the role of cyclic AMP signaling underlying the effects of PACAP. PACAP38 induced accumulation of cyclic AMP in astrocytes at concentrations as low as 10(-12)M. PACAP38 (10(-12)-10(-9)M)-stimulated cell proliferation was completely abolished by the cyclic AMP antagonist Rp-cAMP, whereas the protein kinase A (PKA) inhibitor H89 had no effect. This PACAP38-mediated effect was also abolished by the ERK kinase inhibitor PD98059, suggesting the involvement of ERK in PACAP-induced proliferation. PACAP38 (10(-12)M)-stimulated phosphorylation of ERK lasted for at least 60 min. This effect was completely abolished by Rp-cAMP but not by H89. Dibutyryl cyclic AMP maximally stimulated the incorporation of thymidine and activation of ERK at 10(-10)M. These results suggest that PACAP-mediated stimulation of ERK activity and proliferation of astrocytes may involve a cyclic AMP-dependent, but PKA-independent, pathway.