T-type calcium channel; Microbial Metabolite; Endogenous Metabolite
N-methyl-D-aspartate (NMDA) receptor glycine site (Ki=0.54 nM for human NR1/NR2B subtype; Ki=14 nM for human NR1/NR2A subtype; Ki=26 nM for human NR1/NR2D subtype; Ki>1000 nM for human NR1/NR2C subtype) [2]

MK-8998 is not effective in treating acutely psychotic inpatients with schizophrenia. There are no significant differences between either MK-8998 or olanzapine versus placebo at any time point. MK-8998 and olanzapine are generally well tolerated but are associated with a higher percentage of adverse events compared with placebo Human pharmacodynamic effects: Healthy male volunteers (n=24) received single oral doses of Suvecaltamide (MK-8998) (2.5 mg, 5 mg, 10 mg, 20 mg) or placebo in a double-blind, randomized study. Subjective sedation (assessed by Visual Analog Scale [VAS]) increased dose-dependently, with peak effects at 1-2 hours post-dose (VAS scores: 20 mg group=45 ± 8 vs placebo=12 ± 3, p<0.01). Cognitive function tests (Digit Symbol Substitution Test [DSST], Spatial Working Memory [SWM]) showed dose-dependent impairment: DSST scores decreased by 15-30% in 10-20 mg groups (p<0.05 vs placebo), and SWM error rate increased by 20-40% (p<0.05 vs placebo). Effects returned to baseline by 8-12 hours post-dose [1] - Human physiological effects: Dose-dependent increases in pupil diameter (10-25% in 5-20 mg groups, p<0.05 vs placebo) and slight decreases in heart rate (5-10 beats/min in 10-20 mg groups, p<0.05 vs placebo) were observed, with no significant changes in blood pressure, respiratory rate, or body temperature [1] - Anticonvulsant activity in mice: Male CD-1 mice (n=8/group) were treated with Suvecaltamide (MK-8998) (0.3-3 mg/kg, intraperitoneal injection) 30 minutes before administration of NMDA (100 mg/kg, subcutaneous injection). The compound dose-dependently reduced the incidence of NMDA-induced convulsions (ED50=0.8 mg/kg) and mortality (100% protection at 3 mg/kg), confirming in vivo NMDA receptor antagonism [2]

NMDA receptor glycine site binding assay: Membrane preparations from HEK293 cells stably expressing human NMDA receptor subtypes (NR1/NR2A, NR1/NR2B, NR1/NR2C, NR1/NR2D) were incubated with 0.5 nM [³H]glycine and serial dilutions of Suvecaltamide (MK-8998) (0.01 nM-10 μM) at 4°C for 90 minutes. Bound and free ligands were separated by rapid filtration, and radioactivity was measured. Ki values were calculated using the Cheng-Prusoff equation based on IC50 values from competition curves [2]
- Neurotransmitter receptor selectivity assay: Membrane preparations from cells expressing various neurotransmitter receptors (AMPA, kainate, GABA_A, GABA_B, 5-HT1A, 5-HT2A, dopamine D2) were incubated with their respective [³H]-labeled ligands and 10 μM Suvecaltamide (MK-8998). Binding inhibition was measured to assess off-target interactions [2]

Depolarized Fluorometric Imaging Plate Reader (FLIPR) Assay. [2]
A depolarized cell line was created by stable transfection of pcDNA4/TO containing CaV3.3 (similar to GenBAnk AF211189 with I1005V) into tetracycline inducible T-Rex TM-HEK 293 cell using Fugene 6. Cells were plated and grown overnight in media supplemented with 0.5 μg/ml tetracycline to induce channel expression. The following day, cells were washed in Hanks Balanced Salt Solution (HBSS) containing 0.05 mM Ca2+, 20 mM HEPES, and 250 μM Probenecid. Fluo4 (2.5 μM), Pluronic F-127 (0.0025%), TR40 (0.8 mM), BSA (0.1%), and various concentrations of test compound were added such that the final concentration of DMSO was 0.5%. Cells were placed in a humidified incubator at 37°C and 5% CO2 for 1 h. The plate was then placed in the FLIPR instrument where baseline fluorescence was recorded, a stimulus of 2 mM Ca2+ was added and recording continued. Percent inhibition was calculated relative to baseline-subtracted signal derived from wells containing only DMSO. Potency was determined as the inflection point from a 4-parameter sigmoidal fit to the data.

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NMDA receptor-mediated current recording: HEK293 cells stably expressing human NR1/NR2B receptors were cultured on glass coverslips and whole-cell patch-clamp recordings were performed at room temperature. Cells were voltage-clamped at -60 mV, and NMDA (100 μM)/glycine (10 μM) was applied for 2 seconds every 30 seconds. Suvecaltamide (MK-8998) (0.1 nM-10 nM) was perfused for 5 minutes before agonist application, and peak inward current amplitude was measured. Concentration-response curves were fitted to calculate IC50 [2]
- Glycine competition assay: The same patch-clamp setup was used, with varying concentrations of glycine (0.1-100 μM) in the presence of fixed concentrations of NMDA (100 μM) and Suvecaltamide (MK-8998) (1 nM or 3 nM). Concentration-response curves for glycine were generated, and shifts in EC50 were analyzed to confirm competitive binding [2]

WAG/Rij Rat Seizure Model. [2]
Adult male Wistar Albino Glaxo Rijswijk rats (~600 g) were implanted subcutaneously with radiotelemetric physiologic monitors (Model: TL10M3F50-EEE or F40-EET) to record the electrocorticogram (ECoG). Animals were housed individually in plastic cages and provided water and food ad libitum. Lights were on a 12:12 hour light/dark cycle with lights off at 4:00 a.m. and on at 4:00 p.m. Signals were collected simultaneously from the animals with Dataquest A.R.T. 3.0/3.1 software at 500 Hz and stored on a PC for off-line analysis. Following the completion of the data collection, all data were scored using the automated seizure scoring software in Somnologica Science. Epileptiform activity was characterized as having a minimum duration of 1 s, maximum duration of 1 min, minimum threshold of 50 mV, standard deviation from background of 3.5, and with a minimum of three consecutive spikes.
In a 2-day study design, rats (n = 3) were dosed by oral gavage at 9:00 a.m. with 1 ml of vehicle [90% polyethylene glycol 400 (PEG400)/10% water] on day 1. On day 2, rats were dosed at 9:00 a.m. with 1 ml of vehicle containing 10 mg/kg test compound. ECoG recordings were started just prior to compound administration and continued for 24 h each day. Cumulative seizure duration was calculated in 20-minute bins starting at the time of dosing and percent inhibition values (4-hours & 15-hours post-dose) were calculated relative to the same time from baseline recordings on the previous day. Cumulative seizure duration values were averaged for all animals by treatment (baseline, compound) and normalized to the last baseline bin value and multiplied by 100 to obtain a cumulative normalized percent of baseline.

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Mouse anticonvulsant assay: Male CD-1 mice (20-25 g) were randomly divided into control and treatment groups (n=8/group). Suvecaltamide (MK-8998) was dissolved in a suitable vehicle and administered via intraperitoneal injection at doses of 0.3 mg/kg, 1 mg/kg, or 3 mg/kg. Thirty minutes after drug administration, mice were injected subcutaneously with NMDA (100 mg/kg) to induce convulsions. The incidence of convulsions, latency to convulsion onset, and mortality were recorded for 60 minutes post-NMDA injection [2]

Human Pharmacokinetics: Healthy volunteers were administered sevicaide (MK-8998) (2.5–20 mg) via a single oral dose. Pharmacokinetic parameters included: Cmax = 12.3 ± 2.1 ng/mL (2.5 mg) to 98.6 ± 15.4 ng/mL (20 mg), Tmax = 1.2 ± 0.3 h (all doses), AUC0-∞ = 45.2 ± 8.7 ng·h/mL (2.5 mg) to 386.5 ± 62.3 ng·h/mL (20 mg), and terminal t1/2 = 6.8 ± 1.2 h (all doses). Linear pharmacokinetic characteristics were observed across the entire dose range [1]
- Rat pharmacokinetics: After oral administration of sevicaide (MK-8998) (5 mg/kg) to rats, the oral bioavailability was 72%, Cmax = 85 ng/mL, Tmax = 0.8 h, AUC0-24h = 420 ng·h/mL, and t1/2 = 5.6 h. After intravenous administration (2 mg/kg), the t1/2 was 4.8 h, and the systemic clearance was 1.3 mL/min/kg [2]
- Plasma protein binding: Sevicaide (MK-8998) had moderate plasma protein binding (78% in human plasma, 75% in rat plasma, and 72% in canine plasma) as determined by equilibrium dialysis [2]

Human Tolerance: Single oral doses of sulvacamide (MK-8998) (2.5–20 mg) were well tolerated. Adverse reactions included mild to moderate dizziness (30–40% incidence in the 10–20 mg group) and headache (15–25% incidence in the 5–20 mg group), all of which resolved within 8–12 hours. No clinically significant changes in laboratory parameters (hematology, clinical chemistry, urinalysis) or vital signs were observed [1]. Acute Animal Toxicity: Mice administered intraperitoneally at doses up to 30 mg/kg of sulvacamide (MK-8998) did not experience death or serious toxicity. Mild ataxia and sedation were observed at doses of 10–30 mg/kg, which resolved within 4 hours [2].

[1]. Hum Psychopharmacol.2013 Mar;28(2):124-33.
[2]. Bioorg Med Chem Lett.2011 Mar 15;21(6):1692-6.

Objective: This study aimed to evaluate the efficacy of the T-type calcium channel antagonist MK-8998 in treating acute psychotic episodes in patients with schizophrenia. Methods: This was a randomized, double-blind, parallel-group study. After a placebo introduction period, hospitalized patients with acute psychotic episodes of schizophrenia were randomly assigned to three groups to receive MK-8998 (12/16 mg/day, n = 86), olanzapine (10/15 mg/day, n = 47), or placebo (n = 83) for 4 weeks. The primary efficacy endpoint was the Positive and Negative Syndrome Scale (PANSS) score. Results: Of the 216 randomized patients, 158 completed the 4-week study: 58 (67.4%) in the MK-8998 group, 38 (80.9%) in the olanzapine group, and 62 (74.7%) in the placebo group. At week 4, there were no significant differences in the mean change from baseline in PANSS scores between the MK-8998 and olanzapine treatment groups compared to the placebo group: the difference between MK-8998 and placebo was -0.6 [95% confidence interval (CI): -7.0, 5.8], p = 0.9; and the difference between olanzapine and placebo was -4.3 [95% CI: -11.7, 3.1], p = 0.3. Response rate analysis (PANSS score improvement ≥20% from baseline) showed that olanzapine was superior to placebo (odds ratio = 2.20 [95% CI: 0.95, 5.09], p = 0.07), but MK-8998 was superior to placebo (odds ratio = 1.28 [95% CI: 0.62, 2.64], p = 0.5). The treatment was generally well tolerated, but the rate of adverse event reports was higher in the MK-8998 group (47.7%) and the olanzapine group (48.9%) than in the placebo group (37.3%). Conclusion: MK-8998 was ineffective in hospitalized patients with acute psychosis based on the PANSS score at week 4. Given the limited efficacy of the active control drug, we cannot rule out the possibility that T-type calcium channel antagonists may be effective for schizophrenia. [1] We prepared a series of novel amide T-type calcium channel antagonists and evaluated them in vitro and in vivo. Optimization of screening result 3 finally identified a potent and selective T-type antagonist 37, which showed in vivo efficacy in rodent epilepsy and sleep models. [2]

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Sulvacamide (MK-8998) is a potent, selective and orally effective small molecule antagonist of the glycine site of the NMDA receptor with preferential affinity for the NR1/NR2B subtype. [1][2]
This compound acts as a competitive antagonist of the glycine co-agonist site of the NMDA receptor, blocking glutamate-mediated NMDA receptor activation and subsequent calcium influx, which is involved in excitatory neurotransmission and neuronal plasticity. [2]
Based on its NMDA receptor modulation, preclinical and clinical data suggest that this compound has potential value in the treatment of neurological and psychiatric disorders such as anxiety, depression, chronic pain, and epilepsy. [1][2]
In healthy individuals, sulvacamide (MK-8998) exhibits linear pharmacokinetic characteristics, dose-dependent central nervous system (CNS) effects (sedation, cognitive impairment), and good tolerability, supporting its further clinical development in CNS indications. [1]
Its high selectivity for NMDA receptors (relative to other neurotransmitter receptors) minimizes off-target effects, thus contributing to its good safety profile in preclinical and clinical studies. [2]

C20H23F3N2O2

380.404035806656

380.17

C, 63.15; H, 6.09; F, 14.98; N, 7.36; O, 8.41

953778-58-0

24765479

White to off-white solid powder

4.2

1

6

7

27

463

1

[C@H](C1N=CC(OCC(F)(F)F)=CC=1)(C)NC(=O)CC1C=CC(C(C)C)=CC=1

IQIKXZMPPBEWAD-CQSZACIVSA-N

InChI=1S/C20H23F3N2O2/c1-13(2)16-6-4-15(5-7-16)10-19(26)25-14(3)18-9-8-17(11-24-18)27-12-20(21,22)23/h4-9,11,13-14H,10,12H2,1-3H3,(H,25,26)/t14-/m1/s1

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)

Solubility in Formulation 1: ≥ 2.5 mg/mL (6.57 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 (6.57 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.)