NMDA Receptor
Traxoprodil is a selective antagonist of the NR2B subunit of the N-methyl-D-aspartate (NMDA) receptor. [2]

(1S,2S)-1-(4-Hydroxyphenyl)-2-(4-hydroxy-4-phenylpiperidino)-1-propanol (20, CP-101,606) has been identified as a potent and selective N-methyl-D-aspartate (NMDA) antagonist through a structure activity relation (SAR) program based on ifenprodil, a known antihypertensive agent with NMDA antagonist activity. Sites on the threo-ifenprodil skeleton explored in this report include the pendent methyl group (H, methyl, and ethyl nearly equipotent; propyl much weaker), the spacer group connecting the C-4 phenyl group to the piperidine ring (an alternating potency pattern with 0 and 2 carbon atoms yielding the greatest potency), and simple phenyl substitution (little effect). While potent NMDA antagonists were obtained with a two atom spacer, this arrangement also increased alpha 1 adrenergic affinity. Introduction of a hydroxyl group into the C-4 position on these piperidine ring resulted in substantial reduction in alpha 1 adrenergic affinity. The combination of these observations was instrumental in the discovery of 20. This compound potently protects cultured hippocampal neurons from glutamate toxicity (IC50 = 10 nM) while possessing little of the undesired alpha 1 adrenergic affinity (IC50 approximately 20 microM) of ifenprodil. Furthermore, 20 appears to lack the psychomotor stimulant effects of nonselective competitive and channel-blocking NMDA antagonists. Thus, 20 shows great promise as a neuroprotective agent and may lack the side effects of compounds currently in clinical trials[1].

Traxoprodil (20 nM icv) increases systemic tonic tetanes induced by PTZ (70 mg/kg; i.p.); Traxoprodil (60 mg/kg, coal) prolongs the potential period of tetanic recovery and fullness and reduces the total expected benefit time[3]. Traxoprodil demonstrated antidepressant activity in the forced swim test at doses of 20 and 40 mg/kg and was associated with changes in animal locomotion [2].

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Polyamines, including spermidine, facilitate seizures by positively modulating N-methyl-d-aspartate receptors (NMDAr). Although NMDAr antagonists decrease seizures, it remains to be determined whether traxoprodil, a selective antagonist at the NR2B subunit of the NMDAr, decreases seizures and whether spermidine facilitates pentylenetetrazol (PTZ)-induced seizures. Adult male Wistar rats were injected in the lateral ventricle with 0.9% NaCl (1μl, i.c.v.), spermidine (0.02, 0.2 or 2nmol/site, i.c.v.) or traxoprodil (0.2, 2 or 20nmol, i.c.v.) and with PTZ (35 or 70mg/kg, i.p.). The effect of orally administered traxoprodil (60mg/kg, p.o.) on seizures was also investigated. Latencies to clonic and generalized seizures, as well the total time spent in seizures were recorded by behavioral and electrographic methods (EEG). Spermidine (2nmol/site; i.c.v.) facilitated the seizures induced by a sub-threshold dose of PTZ (35mg/kg; i.p.), but did not alter seizure activity induced by a convulsant dose of PTZ (70mg/kg; i.p.). Traxoprodil (20nmol i.c.v.) increased the latency to generalized tonic-clonic seizures induced by PTZ (70mg/kg; i.p.). Traxoprodil (60mg/kg, p.o.) increased the latency to clonic and generalized seizures, and decreased the total time spent in seizures. These results support the role for the NR2B subunit in PTZ-induced seizures.[3]

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In the forced swim test (FST) in mice, traxoprodil administered at doses of 20 and 40 mg/kg significantly reduced the total immobility time, indicating antidepressant-like activity. Doses of 5 and 10 mg/kg were ineffective. [2]
The antidepressant-like effect of traxoprodil at 20 mg/kg was partially reversed by pre-treatment with the serotonin synthesis inhibitor p-chlorophenylalanine (p-CPA), suggesting partial involvement of the serotonergic system. [2]
Co-administration of an inactive dose of traxoprodil (10 mg/kg) with subtherapeutic doses of imipramine (15 mg/kg), fluoxetine (5 mg/kg), or escitalopram (2 mg/kg) significantly reduced immobility time in the FST, indicating potentiation of the antidepressant effects of these drugs. [2]
Co-administration of traxoprodil (10 mg/kg) with reboxetine (2.5 mg/kg) did not produce a significant reduction in immobility time. [2]
Pre-treatment with the selective 5-HT_1A receptor antagonist WAY 100,635 (0.1 mg/kg) or the selective 5-HT₂ receptor antagonist ritanserin (4 mg/kg) did not reverse the antidepressant-like effect of traxoprodil (20 mg/kg) in the FST. [2]
Traxoprodil at all tested doses (5, 10, 20, 40 mg/kg) did not significantly affect spontaneous locomotor activity in mice, indicating that its behavioral effects in the FST were not due to stimulant activity. [2]
Co-administration of traxoprodil with imipramine, fluoxetine, escitalopram, or reboxetine, as well as with p-CPA, WAY 100,635, or ritanserin, did not significantly affect locomotor activity. [2]

Traxoprodil (5, 10, 20, and 40 mg/kg) was suspended in a 1 % aqueous solution of Tween 80 (POCH), whereas imipramine hydrochloride (15 and 30 mg/kg), fluoxetine hydrochloride (5 mg/kg), escitalopram oxalate (2 mg/kg), reboxetine mesylate (2.5 mg/kg), WAY 100,635 (0.1 mg/kg), and ritanserin (4 mg/kgh) were dissolved in physiological saline (0.9 % NaCl). The solutions/suspension were prepared immediately prior to the experiments and were administered intraperitoneally (i.p.) 60 min before testing. The doses and pretreatment schedules were selected on the basis of the literature data and the results of our previous experiments (Poleszak et al. 2005, 2007a, 2011, 2013; Szewczyk et al. 2002, 2009). Animals from the control groups received i.p. injections of the vehicle (saline). The volume of all administered solutions/suspension was 10 ml/kg.[2]

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Adult male Albino Swiss mice (25-30 g) were used. Traxoprodil was suspended in a 1% aqueous solution of Tween 80. Imipramine hydrochloride, fluoxetine hydrochloride, escitalopram oxalate, reboxetine mesylate, WAY 100,635, and ritanserin were dissolved in physiological saline (0.9% NaCl). All drugs were administered intraperitoneally (i.p.) in a volume of 10 ml/kg, 60 minutes before behavioral testing. [2]
For the forced swim test, each mouse was placed in a glass cylinder containing water (23-25°C) for 6 minutes, and the total immobility time during the last 4 minutes was recorded. [2]
For locomotor activity assessment, animals were placed in activity chambers, and the distance traveled was recorded between the 2nd and 6th minutes. [2]
For serotonergic lesion, p-chlorophenylalanine (p-CPA) was dissolved in saline and administered i.p. at 200 mg/kg for 3 consecutive days. On the fourth day, mice were given traxoprodil (20 mg/kg) or saline 60 minutes before the FST. [2]
For pharmacokinetic studies, drugs were administered i.p., and mice were decapitated 60 minutes later. Brains were collected, weighed, homogenized in buffer, and drug concentrations were determined using HPLC with fluorescence detection. [2]

Metabolism/Metabolites
The known metabolites of trosoprodil include 4-[1-hydroxy-2-(4-hydroxy-4-phenylpiperidin-1-yl)propyl]phenyl-1,2-diol.

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Combined administration of trosoprodil (10 mg/kg) with imipramine (15 mg/kg) significantly increased the concentrations of imipramine and its metabolite desipramine in the brain compared with imipramine alone. [2]
Combined administration of trosoprodil (10 mg/kg) with escitalopram (2 mg/kg) significantly increased the concentrations of escitalopram and trosoprodil in the brain compared with imipramine alone. [2]
Combined administration of trosoprodil (10 mg/kg) with fluoxetine (5 mg/kg) did not significantly alter the brain concentration of fluoxetine, but significantly increased the brain concentration of trosoprodil compared with trosoprodil alone. [2]
Combination administration of trisoprodil (10 mg/kg) with imipramine (15 mg/kg) did not significantly alter the brain concentration of trisoprodil. [2]

[1]. (1S,2S)-1-(4-hydroxyphenyl)-2-(4-hydroxy-4-phenylpiperidino)-1-propanol: a potent new neuroprotectant which blocks N-methyl-D-aspartate responses. J Med Chem. 1995 Aug 4;38(16):3138-45.

[2]. Traxoprodil, a selective antagonist of the NR2B subunit of the NMDA receptor, potentiates the antidepressant-like effects of certain antidepressant drugs in the forced swim test in mice. Metab Brain Dis. 2016 Aug;31(4):803-14.

[3]. Traxoprodil decreases pentylenetetrazol-induced seizures. Epilepsy Res. 2012 Jun;100(1-2):12-9.

Metabolism / Metabolites:
Known human metabolites of trosoprodil include 4-[1-hydroxy-2-(4-hydroxy-4-phenylpiperidin-1-yl)propyl]phenyl-1,2-diol.

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Trosoprodil is one of the most recently discovered substances with antidepressant activity; it is a selective antagonist of the NMDA receptor NR2B subunit. The primary objective of this study was to evaluate the effects of trosoprodil on animal behavior using a forced swimming test (FST), and the effects of trosoprodil (10 mg/kg) on the activity of antidepressants such as imipramine (15 mg/kg), fluoxetine (5 mg/kg), escitalopram (2 mg/kg), and reboxetine (2.5 mg/kg). To assess the role of the serotonergic system in the antidepressant effect of trosoprodil, we performed a serotonergic impairment assay using selective serotonergic receptor agonists of 5-HT1A and 5-HT2. The concentrations of the test drug in the brain were determined using high-performance liquid chromatography (HPLC). Results showed that trosoprodil exhibited antidepressant activity at doses of 20 and 40 mg/kg, independent of changes in animal motor activity. Co-administration of trosoprodil with subtherapeutic doses of imipramine, fluoxetine, or escitalopram significantly affected animal behavior in the forced swimming test (FST), and importantly, these changes were not related to the severity of motor activity. The observed trosoprodil effects were only partially related to the serotonergic system and were independent of effects on 5-HT1A and 5-HT2 serotonin receptors. An attempt to assess the interaction properties of trosoprodil with the test drug indicated that an interaction exists at the pharmacokinetic stage when trosoprodil is co-administered with fluoxetine, imipramine, or escitalopram. [2]

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Trosoprotidel antagonizes the activity of NR1/NR2B NMDA receptor channels by shortening their opening time and frequency, thereby preventing excessive calcium influx into neurons. [2]
Its binding sites are mainly located in the forebrain, hippocampus, and extracortical layer. [2]
It is an analogue of isofenprodil, but has no activity against α1-adrenergic receptors. [2]
Its antidepressant-like mechanism of action is only partially related to the serotonergic system and is independent of the regulation of 5-HT1A and 5-HT2 receptors. [2]
The interaction between trosoprodil and the tested antidepressants (imipramine, fluoxetine, escitalopram) appears to be pharmacokinetic in nature, as evidenced by changes in intracerebral drug concentrations. [2]
Trosoprotidel is metabolized through the cytochrome P450 system and can affect the activity of CYP2D6 isoenzymes. [2]

C20H25NO3

327.4174

327.183

C, 73.37; H, 7.70; N, 4.28; O, 14.66

134234-12-1

Traxoprodil mesylate;188591-67-5

219101

White to off-white solid powder

1.2±0.1 g/cm3

534.4±50.0 °C at 760 mmHg

290.3±28.8 °C

0.0±1.5 mmHg at 25°C

1.626

1.75

3

4

4

24

380

2

C[C@@H]([C@H](C1=CC=C(C=C1)O)O)N2CCC(CC2)(C3=CC=CC=C3)O

QEMSVZNTSXPFJA-HNAYVOBHSA-N

InChI=1S/C20H25NO3/c1-15(19(23)16-7-9-18(22)10-8-16)21-13-11-20(24,12-14-21)17-5-3-2-4-6-17/h2-10,15,19,22-24H,11-14H2,1H3/t15-,19+/m0/s1

1-((1S,2S)-1-hydroxy-1-(4-hydroxyphenyl)propan-2-yl)-4-phenylpiperidin-4-ol

CP-101606; CP-98113; CP101606; 1-((1S,2S)-1-hydroxy-1-(4-hydroxyphenyl)propan-2-yl)-4-phenylpiperidin-4-ol; CP-101,606; Traxoprodil [INN]; CP98113; CP 101606; CP101,606; CP 98113.

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 : ~62.5 mg/mL (~190.89 mM)
H2O : ~0.1 mg/mL (~0.31 mM)

Solubility in Formulation 1: ≥ 2.08 mg/mL (6.35 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 20.8 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: ≥ 2.08 mg/mL (6.35 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 20.8 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: ≥ 2.08 mg/mL (6.35 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 20.8 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.)