Search

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.)

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. • TAK-653 stimulated mTOR signaling and BDNF production in primary neurons. • TAK-653 showed antidepressant-like effects in rat RSBM. • Ketamine induced hyperlocomotion, while TAK-653 did not induce hyperlocomotion. • TAK-653 may be a safer drug for treatment of MDD compared with ketamine. [ABSTRACT FROM AUTHOR]

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. • One-day treatment with ketamine shortened the latency to feed in an NSF test. • Three-day treatment with TAK-137 shortened the latency to feed. • Ketamine induced hyperlocomotion and reduced PPI. • TAK-137 did not induce hyperlocomotion or reduce PPI. • Compounds such as TAK-137 may be safer drugs for the treatment of MDD. [ABSTRACT FROM AUTHOR]