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Traxoprodil (CP-101606, CP 98113, and CP101,606) is a novel, potent and selective NMDA (NR2B N-Methyl-D-Aspartate) antagonist with neuroprotective effects. It protects hippocampal neurons with an IC50 of 10 nM and can be potentially used for the treatment of major depression. Traxoprodil potentiates the antidepressant-like effects of certain antidepressant drugs in the forced swim test in mice. Traxoprodil decreases pentylenetetrazol-induced seizures.
Physicochemical Properties
| Molecular Formula | C20H25NO3 |
| Molecular Weight | 327.4174 |
| Exact Mass | 327.183 |
| Elemental Analysis | C, 73.37; H, 7.70; N, 4.28; O, 14.66 |
| CAS # | 134234-12-1 |
| Related CAS # | Traxoprodil mesylate;188591-67-5 |
| PubChem CID | 219101 |
| Appearance | White to off-white solid powder |
| Density | 1.2±0.1 g/cm3 |
| Boiling Point | 534.4±50.0 °C at 760 mmHg |
| Flash Point | 290.3±28.8 °C |
| Vapour Pressure | 0.0±1.5 mmHg at 25°C |
| Index of Refraction | 1.626 |
| LogP | 1.75 |
| Hydrogen Bond Donor Count | 3 |
| Hydrogen Bond Acceptor Count | 4 |
| Rotatable Bond Count | 4 |
| Heavy Atom Count | 24 |
| Complexity | 380 |
| Defined Atom Stereocenter Count | 2 |
| SMILES | C[C@@H]([C@H](C1=CC=C(C=C1)O)O)N2CCC(CC2)(C3=CC=CC=C3)O |
| InChi Key | QEMSVZNTSXPFJA-HNAYVOBHSA-N |
| InChi Code | 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 |
| Chemical Name | 1-((1S,2S)-1-hydroxy-1-(4-hydroxyphenyl)propan-2-yl)-4-phenylpiperidin-4-ol |
| Synonyms | 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. |
| HS Tariff Code | 2934.99.9001 |
| Storage |
Powder-20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
| Shipping Condition | Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs) |
Biological Activity
| Targets |
NMDA Receptor Traxoprodil is a selective antagonist of the NR2B subunit of the N-methyl-D-aspartate (NMDA) receptor. [2] |
| ln Vitro | (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]. |
| ln Vivo |
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]. 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] 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-HT1A 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] |
| Animal Protocol |
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] 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] |
| ADME/Pharmacokinetics |
Metabolism / Metabolites Traxoprodil has known human metabolites that include 4-[1-Hydroxy-2-(4-hydroxy-4-phenylpiperidin-1-yl)propyl]benzene-1,2-diol. Co-administration of traxoprodil (10 mg/kg) with imipramine (15 mg/kg) significantly increased brain concentrations of imipramine and its metabolite desipramine compared to imipramine alone. [2] Co-administration of traxoprodil (10 mg/kg) with escitalopram (2 mg/kg) significantly increased brain concentrations of both escitalopram and traxoprodil compared to the respective single-agent groups. [2] Co-administration of traxoprodil (10 mg/kg) with fluoxetine (5 mg/kg) did not significantly alter fluoxetine brain concentration but significantly increased traxoprodil brain concentration compared to traxoprodil alone. [2] Co-administration of traxoprodil (10 mg/kg) with imipramine (15 mg/kg) did not significantly alter traxoprodil brain concentration. [2] |
| References |
[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. |
| Additional Infomation |
Metabolism / Metabolites: Traxoprodil has known human metabolites that include 4-[1-Hydroxy-2-(4-hydroxy-4-phenylpiperidin-1-yl)propyl]benzene-1,2-diol. One of the newest substances, whose antidepressant activity was shown is traxoprodil, which is a selective antagonist of the NR2B subunit of the NMDA receptor. The main goal of the present study was to evaluate the effect of traxoprodil on animals' behavior using the forced swim test (FST), as well as the effect of traxoprodil (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). Serotonergic lesion and experiment using the selective agonists of serotonin receptors 5-HT1A and 5-HT2 was conducted to evaluate the role of the serotonergic system in the antidepressant action of traxoprodil. Brain concentrations of tested agents were determined using HPLC. The results showed that traxoprodil at a dose of 20 and 40 mg/kg exhibited antidepressant activity in the FST and it was not related to changes in animals' locomotor activity. Co-administration of traxoprodil with imipramine, fluoxetine or escitalopram, each in subtherapeutic doses, significantly affected the animals' behavior in the FST and, what is important, these changes were not due to the severity of locomotor activity. The observed effect of traxoprodil is only partially associated with serotonergic system and is independent of the effect on the 5-HT1A and 5-HT2 serotonin receptors. The results of an attempt to assess the nature of the interaction between traxoprodil and the tested drugs show that in the case of joint administration of traxoprodil and fluoxetine, imipramine or escitalopram, there were interactions in the pharmacokinetic phase.[2] Traxoprodil antagonizes the activity of the NR1/NR2B NMDA receptor channel by shortening its open time and frequency, thereby preventing excessive calcium influx into neurons. [2] Its binding site is mainly located in the forebrain, hippocampus, and outer layers of the cortex. [2] It is an analogue of ifenprodil but lacks activity against α1-adrenergic receptors. [2] The mechanism of its antidepressant-like effect is only partially associated with the serotonergic system and is independent of 5-HT1A and 5-HT2 receptor modulation. [2] The interactions between traxoprodil and the tested antidepressants (imipramine, fluoxetine, escitalopram) appear to be pharmacokinetic in nature, as evidenced by changes in brain drug concentrations. [2] Traxoprodil is metabolized by the cytochrome P450 system and can influence the activity of the CYP2D6 isoenzyme. [2] |
Solubility Data
| Solubility (In Vitro) |
DMSO : ~62.5 mg/mL (~190.89 mM) H2O : ~0.1 mg/mL (~0.31 mM) |
| Solubility (In Vivo) |
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. 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. 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. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 3.0542 mL | 15.2709 mL | 30.5418 mL | |
| 5 mM | 0.6108 mL | 3.0542 mL | 6.1084 mL | |
| 10 mM | 0.3054 mL | 1.5271 mL | 3.0542 mL |