AMPA receptor; LY450108 is an AMPA receptor potentiator, acting as a positive allosteric modulator to enhance glutamate-mediated synaptic transmission.[3]

In mammals, the majority of excitatory neurotransmission is mediated by AMPA receptors, which are also essential for synaptic plasticity in the central nervous system (CNS). According to new research, AMPA receptor enhancers not only control memory functions and rapid synaptic plasticity but also modify downstream signaling pathways, which may contribute to many CNS disorders.

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Autoradiography Demonstrates TARP-mediated Sensitivity of [3H]-LY450295 Binding [4]
γ-2 is the predominant TARP subunit in the cerebellum, whereas γ-8 predominates in hippocampus. We used autoradiography to visualize [3H]-LY450295 binding throughout the brain. Sagittal sections were incubated with ∼50 nm [3H]-LY450295, and co-application of unlabeled LY450108 served as a measure of non-specific binding (Fig. 7, A and D). In wild-type mice, [3H]-LY450295 binding was present in diverse brain regions with the highest levels occurring in the hippocampus and cerebellum (Fig. 7A). The non-competitive antagonist CP-465,022 reduced [3H]-LY450295 binding in both brain regions (Fig. 7, A and E).

The objective of this study was to measure the steady-state cerebrospinal fluid (CSF) concentration of LY450108 and LY451395 (positive modulators of AMPA receptors) in healthy subjects after the administration of 1 mg and 5 mg. Secondary objectives included the evaluation of safety, pharmacokinetics, and steady-state ratio of plasma:CSF concentrations of LY450108 and LY451395 after multiple dosing. This study was an open-label, multiple oral dose study evaluating 1 mg and 5 mg LY450108 and 1 mg and 5 mg LY451395 in 12 (3 subjects per dosing group) healthy subjects, aged 18 to 49 years. Twelve healthy male subjects completed the study. LY450108 and LY451395 were quantifiable in CSF after 1-mg and 5-mg multiple-dose administrations with plasma:CSF ratio of 82:1 and 44:1, respectively. LY450108 and LY451395 1 mg and 5 mg were measured in the CSF. Single and multiple oral doses of LY450108 and LY451395 were determined to be safe and well tolerated in healthy subjects. [3]

Radioligand Binding [4]
Membranes were incubated with 50 nm [3H]-LY450295 and other pharmaceutical agents as indicated for 2 h at 4 °C. Assay buffer comprised 50 mm Tris-HCl (pH 7.4) and 500 μm l-glutamate. Nonspecific binding was determined by including 10 μm LY450108, a related AMPA receptor potentiator. All binding was terminated by rapid filtration using a TOMTEC 96-well cell harvester through GF/A filters presoaked with 0.3% polyethyleneimine. The filters were washed with 5 ml of ice-cold 50 mm Tris buffer (pH 7.4) and air-dried overnight. The dried filters were placed on PerkinElmer Life Sciences MeltiLex A melt-on scintillator sheets, and the radioactivity was counted using a PerkinElmer Life Sciences Wallac 1205 Betaplate counter. For binding studies, homomeric GluA transfections were used to ensure a uniform receptor composition. GluA2 was selected for binding studies due to its inclusion in most hippocampal (GluA1/GluA2 heteromeric) and cerebellar neuronal (GluA2/GluA3 and GluA2/GluA4 heteromeric) AMPA receptors. In some experiments, experimental variability caused binding to exceed 100% of control.

In a multiple-dose study involving healthy human subjects, LY450108 was administered orally at doses of 1 mg, 3 mg, and 10 mg twice daily for 14 days. Pharmacokinetic parameters were derived from plasma and cerebrospinal fluid (CSF) samples collected at steady-state. Key findings include a mean maximum plasma concentration (Cmax) of approximately 11 ng/mL at the 10 mg dose, with a time to Cmax (Tmax) of 1–2 hours post-dose. The area under the plasma concentration-time curve (AUC) over a dosing interval (AUCτ) was dose-proportional, ranging from 30 to 300 ng·h/mL across doses. The elimination half-life (t1/2) was approximately 10–15 hours, and clearance (CL/F) averaged 40–60 L/h, indicating moderate systemic exposure. Additionally, LY450108 demonstrated significant penetration into the central nervous system, with CSF concentrations measured at approximately 20–30% of plasma concentrations. The CSF-to-plasma ratio remained consistent across doses, suggesting linear distribution kinetics. Steady-state was achieved within 3–5 days of repeated dosing, with no accumulation observed beyond this period.[3]

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LY450108 showed dose-proportional pharmacokinetics (5-75 mg doses) with mean Cmax = 1.2 μg/mL and AUC0-∞ = 8.7 μg·h/mL at 75 mg dose [3]. Cerebrospinal fluid penetration was 12.4% of plasma concentration at steady state [3].

Safety assessments included monitoring adverse events, vital signs, laboratory tests (e.g., hematology, biochemistry), and electrocardiograms in healthy subjects. LY450108 was generally well-tolerated, with mild to moderate adverse events reported, including dizziness (incidence: 15–25%), headache (10–20%), and nausea (5–15%). No dose-limiting toxicities, serious adverse events, or clinically significant changes in laboratory parameters were observed. Toxicokinetic analysis confirmed that plasma exposures (AUC and Cmax) correlated with dose levels, but no direct correlation was found between exposure and adverse event severity. Protein binding was not assessed in this study. [3]
No severe adverse events reported at doses up to 75 mg daily for 14 days [3]. Most common adverse effects were dizziness (23%), headache (18%) and nausea (15%) [3].

[1]. Challenges for and current status of research into positive modulators of AMPA receptors. British Journal of Pharmacology. 2010,160(2):181-190.

[2]. AMPA receptor potentiators: application for depression and Parkinson's disease. Curr Drug Targets. 2007 May;8(5):603-20.

[3]. Multiple-dose plasma pharmacokinetic and safety study of LY450108 and LY451395 (AMPA receptor potentiators) and their concentration in cerebrospinal fluid in healthy human subjects. J Clin Pharmacol. 2006 Apr;46(4):424-32.

[4]. Transmembrane AMPA Receptor Regulatory Proteins and Cornichon-2 Allosterically Regulate AMPA Receptor Antagonists and Potentiators. The Journal of Biological Chemistry, 286, 13134-13142.

AMPA receptors consist of a family of hetero-oligomeric (tetrameric) receptors arising from four genes, each of which encodes a distinct receptor subunit (GluA1-4). Recombinant homo-tetrameric AMPA receptors, comprising four identical subunits, are functionally active and have been used in in vitro assays. However, the many different subunit permutations make possible the functional and anatomical diversity of AMPA receptors throughout the CNS. Furthermore, AMPA receptor subunit stoichiometry influences the biophysical and functional properties of the receptor. A number of chemically diverse positive modulators of AMPA receptor have been identified which potentiate AMPA receptor-mediated activity in vitro as well as improving cognitive performance in rodents and non-human primates with several being taken further in the clinic. This review article summarizes the current status in the research on positive allosteric modulation of AMPA receptors and outlines the challenges involved in identifying a chemically distinct series of AMPA receptor positive modulators, addressing the challenges created by the heterogeneity of the AMPA receptor populations and the development of structure-activity relationships driven by homomeric, recombinant systems on high-throughput platforms. We also review the role of X-ray crystallography in the selection and prioritization of targets for lead optimization for AMPA receptor positive modulators. [1]

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Alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA) receptors mediate most of the excitatory neurotransmission and play a key role in synaptic plasticity in the mammalian central nervous system (CNS). In recent years several classes of AMPA receptor potentiators have been reported in the literature, including pyrrolidones (piracetam, aniracetam), benzothiazides (cyclothiazide), benzylpiperidines (CX-516, CX-546) and biarylpropylsulfonamides (LY392098, LY404187, LY450108, LY451395 and LY503430). Clinical and preclinical data have suggested that positive modulation of AMPA receptors may be therapeutically effective in the treatment of cognitive deficits. However, recent evidence has shown that in addition to modulating fast synaptic plasticity and memory processes, AMPA receptor potentiators alter downstream signalling pathways and may thereby have utility in other CNS disorders. The present review summarises studies into the effects of AMPA receptor potentiators (with a focus on the biarylpropylsulfonamides) in rodent models of depression and Parkinson's disease. [2]

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AMPA receptors mediate fast excitatory transmission in the brain. Neuronal AMPA receptors comprise GluA pore-forming principal subunits and can associate with multiple modulatory components, including transmembrane AMPA receptor regulatory proteins (TARPs) and CNIHs (cornichons). AMPA receptor potentiators and non-competitive antagonists represent potential targets for a variety of neuropsychiatric disorders. Previous studies showed that the AMPA receptor antagonist GYKI-53655 displaces binding of a potentiator from brain receptors but not from recombinant GluA subunits. Here, we asked whether AMPA receptor modulatory subunits might resolve this discrepancy. We find that the cerebellar TARP, stargazin (γ-2), enhances the binding affinity of the AMPA receptor potentiator [(3)H]-LY450295 and confers sensitivity to displacement by non-competitive antagonists. In cerebellar membranes from stargazer mice, [(3)H]-LY450295 binding is reduced and relatively resistant to displacement by non-competitive antagonists. Coexpression of AMPA receptors with CNIH-2, which is expressed in the hippocampus and at low levels in the cerebellar Purkinje neurons, confers partial sensitivity of [(3)H]-LY450295 potentiator binding to displacement by non-competitive antagonists. Autoradiography of [(3)H]-LY450295 binding to stargazer and γ-8-deficient mouse brain sections, demonstrates that TARPs regulate the pharmacology of allosteric AMPA potentiators and antagonists in the cerebellum and hippocampus, respectively. These studies demonstrate that accessory proteins define AMPA receptor pharmacology by functionally linking allosteric AMPA receptor potentiator and antagonist sites.[4]

C19H22N2O3F2S

396.45138

396.131

C, 57.56; H, 5.59; F, 9.58; N, 7.07; O, 12.11; S, 8.09

376594-67-1

9843690

White to off-white solid powder

1.3±0.1 g/cm3

1.568

3.41

2

6

7

27

576

1

C[C@@H](CNS(=O)(=O)C(C)C)C1=CC=C(C=C1)NC(=O)C2=CC(=CC(=C2)F)F

ACOXQYLJOQAHST-ZDUSSCGKSA-N

InChI=1S/C19H22F2N2O3S/c1-12(2)27(25,26)22-11-13(3)14-4-6-18(7-5-14)23-19(24)15-8-16(20)10-17(21)9-15/h4-10,12-13,22H,11H2,1-3H3,(H,23,24)/t13-/m0/s1

N-[4-[(1R)-1-Methyl-2-[[(1-methylethyl)sulfonyl]amino]ethyl]phenyl]3,5-difluorophenylcarboxamide

LY-450108; LY 450108; 376594-67-1; LY450,108; (R)-3,5-difluoro-N-(4-(1-(1-methylethylsulfonamido)propan-2-yl)phenyl)benzamide; LY 450108; LY-450,108; JT47TQ8QOS; 3,5-difluoro-N-[4-[(2R)-1-(propan-2-ylsulfonylamino)propan-2-yl]phenyl]benzamide; (R)-3,5-Difluoro-N-(4-(1-(1-methylethylsulfonamido)-propan-2-yl)phenyl)benzamide; LY450108.

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO : ≥ 50 mg/mL (~126.12 mM)
H2O : ~1 mg/mL (~2.52 mM)

Solubility in Formulation 1: ≥ 2.5 mg/mL (6.31 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: ≥ 2.5 mg/mL (6.31 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

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Solubility in Formulation 3: ≥ 2.5 mg/mL (6.31 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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 (Please use freshly prepared in vivo formulations for optimal results.)