 Chemical Structure.png)
Physicochemical Properties
| Molecular Formula | C21H27NO2.1/2C4H6O6 |
| Molecular Weight | 400.50 |
| Elemental Analysis | C, 68.98; H, 7.55; N, 3.50; O, 19.97 |
| CAS # | 1312991-83-5 |
| Related CAS # | 23210-58-4; 23210-56-2 |
| PubChem CID | 90488783 |
| Appearance | Typically exists as solid at room temperature |
| Hydrogen Bond Donor Count | 16 |
| Hydrogen Bond Acceptor Count | 24 |
| Rotatable Bond Count | 26 |
| Heavy Atom Count | 116 |
| Complexity | 487 |
| Defined Atom Stereocenter Count | 8 |
| SMILES | O[C@@H](C1C=CC(=CC=1)O)[C@H](C)N1CCC(CC2C=CC=CC=2)CC1.O[C@@H](C1C=CC(=CC=1)O)[C@H](C)N1CCC(CC2C=CC=CC=2)CC1.O[C@H](C1C=CC(=CC=1)O)[C@@H](C)N1CCC(CC2C=CC=CC=2)CC1.O[C@H](C1C=CC(=CC=1)O)[C@@H](C)N1CCC(CC2C=CC=CC=2)CC1.OC(C(=O)O)C(C(=O)O)O.OC(C(=O)O)C(C(=O)O)O |
| InChi Key | MMUFFGLAKFWLGJ-RRQZTXAJSA-N |
| InChi Code | InChI=1S/4C21H27NO2.2C4H6O6/c4*1-16(21(24)19-7-9-20(23)10-8-19)22-13-11-18(12-14-22)15-17-5-3-2-4-6-17;2*5-1(3(7)8)2(6)4(9)10/h4*2-10,16,18,21,23-24H,11-15H2,1H3;2*1-2,5-6H,(H,7,8)(H,9,10)/t4*16-,21+;;/m1100../s1 |
| Chemical Name | 4-[(1S,2S)-2-(4-benzylpiperidin-1-yl)-1-hydroxypropyl]phenol;4-[(1R,2R)-2-(4-benzylpiperidin-1-yl)-1-hydroxypropyl]phenol;2,3-dihydroxybutanedioic acid |
| Synonyms | (1S*,2S*)-THREO-2-(4-BENZYLPIPERIDINO)-1-(4-HYDROXYPHENYL)-1-PROPANOL HEMITARTRATE; 692-171-9; threo Ifenprodil hemitartrate; 1312991-83-5; 4-[(1S,2S)-2-(4-benzylpiperidin-1-yl)-1-hydroxypropyl]phenol;4-[(1R,2R)-2-(4-benzylpiperidin-1-yl)-1-hydroxypropyl]phenol;2,3-dihydroxybutanedioic acid; (1S*,2S*)-threo-2-(4-Benzylpiperidino)-1-(4-hydroxyphenyl)-1-propanolhemitartrate; |
| 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 (IC50: 0.22 μM) |
| ln Vitro |
The NMDA receptor antagonist ifenprodil contains two asymmetric centres which give rise to four stereoisomeric forms of this molecule. The inhibitory effects of each of these stereoisomers on recombinant NMDA receptors expressed from NR1A/NR2A and NR1A/NR2B subunit combinations were studied in Xenopus oocytes by voltage-clamp recording. All four ifenprodil stereoisomers were potent antagonists at NR1A/NR2B (IC50 < 0.8 microM), but weak antagonists at NR1A/NR2A receptors (IC50 > 100 microM). In heteromeric NR1A/NR2B receptors, (+) erythro- and (-) threo-ifenprodil (IC50 0.21 and 0.22 microM, respectively) were about 4 times more potent than (-) erythro- and (+) threo-ifenprodil (IC50 0.81 and 0.76, respectively). These results show that the stereoisomers of ifenprodil exhibit a weak though significant stereoselectivity at the NR1A/NR2B NMDA receptor subtype [2]. The sigma(2)-receptor agonist, ifenprodil, was suggested as an inhibitor of G protein-coupled inwardly rectifying potassium channels. Nevertheless, an analysis of the role of sigma(2) receptors in cardiac electrophysiology has never been done. This work aims i) to identify the roles of cardiac sigma(2) receptors in the regulation of cardiac K(+) channel conductances and ii) to check whether sigma(2)-receptor agonists exhibit class III antiarrhythmic properties. The sigma(2)-receptor agonists ifenprodil, threo-ifenprodil, LNP250A [threo-8-[1-(4-hydroxyphenyl)-1-hydroxy-propan-2-yl]-1-phenyl-1,3,8-triazaspiro[4,5]decane-4-one] (a derivative of ifenprodil devoid of alpha(1)-adrenergic and N-methyl-d-aspartate glutamate receptor-blocking properties), and 1,3-di(2-tolyl)guanidine were used to discriminate the effects linked to sigma(2) receptors from those of the sigma(1) subtype, induced by (+/-)-N-allylnormetazocine (SKF-10,047). The sigma(2)-receptor antagonist 3-alpha-tropanyl-2(pCl-phenoxy)butyrate (SM-21) was employed to characterize sigma(2)-mediated effects in patch-clamp experiments [3]. |
| ln Vivo |
Observations of sigma (sigma) receptor heterogeneity have prompted interest in identifying ligands for sigma receptor subtypes. Selective ligands for the sigma-2 are unavailable, but [3H]ifenprodil labels sigma-2 sites. Therefore, isomers and analogues of ifenprodil were compared as potential sigma-2 ligands. threo-ifenprodil and erythro-ifenprodil had high affinity (Ki congruent to 2 nM) for sigma-2 sites; erythro-iodoifenprodil had moderate affinity (Ki congruent to 46 nM); eliprodil had lowest affinity (Ki congruent to 630 nM). Threo-ifenprodil, which has less affinity for alpha 1-adrenoceptors than erythro-ifenprodil, was slightly more selective than erythro-ifenprodil for sigma-2 sites. These results identify threo-ifenprodil as potentially useful for studies of sigma-2 receptors. [1] In rabbits, all sigma(2)-receptor agonists reduced phenylephrine-induced cardiac arrhythmias. They prolonged action potential duration in rabbit Purkinje fibers and reduced human ether-a-go-go-related gene (HERG) K(+) currents. (+)-SKF-10,047 was completely inactive in the last two tests. The effects of threo-ifenprodil were not antagonized by SM-21. In HERG-transfected COS-7 cells, SM-21 potentiated the ifenprodil-induced blockade of the HERG current. These data suggest that sigma(2)-receptor ligands block I(Kr) and that this effect could explain part of the antiarrhythmic properties of this ligands family. Nevertheless, an interaction with HERG channels not involving sigma(2) receptors seems to share this pharmacological property. This work shows for the first time that particular caution has to be taken toward ligands with affinity for sigma(2) receptors. The repolarization prolongation and the early-afterdepolarization can be responsible for "torsades de pointe" and sudden cardiac death. [3] Scatchard analysis of [3H](+)-pentazocine (0.8-100 nM) binding (to 0--1 sites) to rat brain membranes yielded a K d of 13.1 + 4.3 nM and a Bma x of 831 + 18 fmol/mg protein (mean + S.E.M., n = 3). Specific binding of [3H]( +)-pentazocine was potently inhibited by erythro-ifenprodil, threo-ifenprodil, erythro-iodoifenprodil and eliprodil (Fig. 2). The rank order of potencies of drugs in competing with [3H](+)-pentazocine binding was as follows: erythro-ifenprodil (K i = 13.0 + 1.0 nM)> threo-ifenprodil (K i = 59.1 + 3.6 nM) > erythro-iodoifenprodil (K i = 122 ___ 13 nM)> eliprodil (K i = 132 + 26 riM). Inhibition by these four drugs was monophasic with pseudo-Hill coefficients close to unity. Scatchard analysis of [3H]DTG (0.8-100 nM) binding (to 0"-2 sites in the presence of 1 /xM (+)-pentazocine) to rat brain membranes yielded a K d of 40.3 + 1.4 nM and a Bma x of 1240 + 63 fmol/mg protein (mean _ S.E.M., n = 3). Specific binding of [3H]DTG (in the presence of 1 /~M (+)-pentazocine) was inhib- ±ted potently and biphasically by erythro-ifenprodil (K H=1.89 nM, K L=586+272 nM) and threo-ifenprodil (K H = 2.22 + 0.40 nM, K L = 145 + 107 nM). The pseudo-Hill coefficients for erythro-ifenprodil and threo-ifenprodil were far less than unity, suggesting that these two drugs interacted with more than one population of sites (Fig. 2). Competition curves for erythro-ifenprodil and threo-ifenprodil revealed that 79% and 89% of the specific binding, respectively, were to a component that was inhibited with high affinity by these drugs. Inhibition of specific binding of [3H]DTG (in the presence of 1 ~M (+)-pentazocine) by erythro-iodoifenprodil (Ki=46.2+5.0 nM) and eliprodil (Ki=634+ 72 nM) was monophasic with pseudo-Hill coefficients close to unity [1]. |
| Enzyme Assay |
Radioligand Binding Assays. [3] The binding profile of the putative σ ligand LNP250A was evaluated according to the method employed by Ganapathy et al. (1999) for σ1 sites and by Hashimoto and London (1995) for σ2 sites. In brief, σ1-binding experiments... |
| Cell Assay |
Oocytes, stage V-VI were dissected from the ovary of anesthetized (in ice-cold water) Xenopus laeui. Defolliculation of oocytes was performed by treatment, under agitation, with collagenase, 7.5 mg/ml for 30 min at room temperature in a modified Ringer solution (see composition below). Oocytes were then stored for 24 h at 18°C in Barth medium, cDNAs (2 ng of NRIA plus 10 ng of NR2A or NR2B, total volume 20 nl) were pressure-injected directly in the oocyte nuclei using a calibrated injection device (inject + matic). Oocytes were then incubated for 2-5 days at 18°C. For recording, oocytes were transferred in a Perspex chamber superfused at 5 ml/min with a high Ba 2÷ Ringer solution (see composition below). Drugs were applied in the superfusing solution. Oocytes were voltage-clamped to negative voltages (-60 to - 80 mV) via two 3 M KC1 filled electrodes (resistance 0.5 M J2) connected to a GeneClamp 500 amplifier. Currents were digitized on-line at 25 Hz using the Axotape (Axon Instruments) software and the data stored on an optical disk. For analysis and presentation, data were transferred in ASCII format to Fig. P. For IC50 determinations, the least square fitting routine of the same software was used. Fitting was performed using all individual data points and fitting parameters are given with a 95% confidence interval. Values are expressed as means + standard error of the number (n) of oocytes tested. [2] Ifenprodil and its stereoisomers were prepared in the laboratory following procedures previously described (see Chenard et al., 1991 and references cited therein). (+) erythro-Ifenprodil was a tartrate salt; (+) erythro- and (-) erythro-ifenprodil were used as benzoate salts and (+) threo- and (-) threo-ifenprodil were used as free bases. All compounds were diluted in dimethyl sulfoxide (DMSO), the constant final concentration of which was 0.08% except for the 100 and 300 /zM compound concentrations where the DMSO concentration was 0.2 and 0.8%, respectively. No difference was observed in preliminary experiments between the effects of (+) erythro-ifenprodil tartrate and (±) erythro-ifenprodil benzoate, indicating no effect of the accompanying ion [2]. |
| Animal Protocol | Observations of sigma (sigma) receptor heterogeneity have prompted interest in identifying ligands for sigma receptor subtypes. Selective ligands for the sigma-2 are unavailable, but [3H]ifenprodil labels sigma-2 sites. Therefore, isomers and analogues of ifenprodil were compared as potential sigma-2 ligands. Threo-ifenprodil and erythro-ifenprodil had high affinity (Ki congruent to 2 nM) for sigma-2 sites; erythro-iodoifenprodil had moderate affinity (Ki congruent to 46 nM); eliprodil had lowest affinity (Ki congruent to 630 nM). Threo-ifenprodil, which has less affinity for alpha 1-adrenoceptors than erythro-ifenprodil, was slightly more selective than erythro-ifenprodil for sigma-2 sites. These results identify threo-ifenprodil as potentially useful for studies of sigma-2 receptors. |
| ADME/Pharmacokinetics |
Identification and fragmentation of the phase I metabolites in vitro [5] Phase I transformation led to several metabolites including two N-dealkylation products and several M+O metabolites (Fig. 2, supporting information). The N-dealkylated metabolites were identified as 4-benzyl-piperidine (1) and oxidized 4-benzyl-piperidin-2-on (2). The structures of the piperidine metabolites 1 and 2 were identified by fragmentation experiments. The main fragment of both metabolites is the tropylium ion with an exact mass of m/z 91.0510 and m/z 91.0518, respectively (see sup. inf.). Furthermore, six phase I metabolites were identified with m/z 342 [M+O+H]+, caused by introduction of an additional O-atom (Fig. 3a). The metabolites were analyzed with MSn experiments. According to this analysis oxidation took place at the piperidine ring (3), in ortho-, meta- and para-position of the phenyl moiety (4a–4c), in ortho position of the phenol (5), and at the N-atom forming the N-oxide (6, Fig. 3b). The three metabolites 4a–4c showed identical fragmentation pattern, indicating very similar structures. The hydroxy group of the monohydroxylated metabolite 3 was assigned to the piperidine heterocycle. The first hint was the fragment m/z 192. This mass is 16 amu higher than the mass of the corresponding fragment of the parent compound. The subsequent fragmentation led to a fragment with m/z 174, which represents the dehydrated benzylpiperidine. These fragments prove the position of the hydroxy group because the fragment m/z 174 is only possible when the hydroxy group was located in the piperidine moiety (Fig. 4). The N-oxide 6 was identified by the fragments m/z 192.1358 (oxidized benzylpiperidine) and m/z 174 [benzylpiperidine+O+H–H2O]+. Thus the additional O-atom can only be localized at the benzylpiperidine part of Ifenprodil. The slightly increased retention time (10.8 min) compared to Ifenprodil (9.4 min) indicates an N-oxide. N-Oxides are known to have longer retention times then their parent compounds due to their slightly increased lipophilicity. Phase II metabolites found in vitro [5] In phase II reactions Ifenprodil can theoretically be converted into glucuronides, sulfates and methylated catechol derivates as described for traxoprodil. β-Glucuronides and sulfates could be formed directly by reaction of the hydroxy groups present in ifenprodil. Additionally, metabolites from phase I reactions can be conjugated in phase II reactions. Methylated catechol derivates are only possible after formation of catechol derivatives by hydroxylation in o-position of the phenol (compare metabolite 5). The glucuronidation was investigated in vitro by addition of UDPGA to the microsomal incubation mixture without addition of NADPH/H+. The observed signal for the glucuronide 7 [M+Glu+H]+ was recorded in positive and negative ion mode. Fragmentation of the β-glucuronide metabolite 7 in positive mode showed two main fragmentation pathways. Similar to Ifenprodil and its derivatives, loss of water was observed (m/z 484.2346 in positive ion mode). On the other hand glucuronic acid was cleaved off resulting in the fragment m/z 326.2134 ([ifenprodil+H]+). Both fragmentations took place in parallel and led to the same further fragment m/z 308.2040 (see SI). In the negative ion mode analogous fragments were observed. Additionally, the fragments of glucuronic acid were identified in negative ion mode. The fragment m/z 193 represents the glucuronate anion, whilst m/z 175 corresponds to a dehydrated glucuronic acid. Subsequent loss of water and CO2 led to fragment m/z 113 which is characteristic for glucuronides (Fig. 5). The incubation of Ifenprodil with NADPH/H+ and UDPGA resulted in the additional glucuronide 8 (Fig. 2), which occurred after glucuronidation of the catechol 5, which was produced during phase I biotransformation. The same catechol 5 could also be methylated by catechol O-methyl transferases. The addition of S-adenosyl methionine (SAM) and NADPH/H+ to the incubation mixture resulted in the formation of a compound with m/z 356.1965, corresponding to the mass of the methylated catechol 9. The fragmentation of 9 (Fig. 6) proceeded analogously to the fragmentation of ifenprodil (see Fig. 1). The formation of the fragment m/z 176.1444 corresponding to the unsubstituted benzylpiperidine dearly proves that the methoxylation had occurred at the phenol moiety and is not the result of a methoxylation of the benzyl moiety. Moreover, the mass of the fragments m/z 338.2129, 163 and 137 are 30 amu higher than the mass of the corresponding ifenprodil fragments. Identification of metabolites formed in vivo [5] For in vivo metabolites the urine of one rat was collected for 48 h in three periods (0–8 h, 8–24 h and 24–48 h) after i.p. injection of 20 mg Ifenprodil/kg rat. The identified metabolites are shown in Fig. 7. Three types of metabolites (11, 12 and 13) were found only in vivo. Metabolite 11 is the result of o-hydroxylation, methylation and glucuronidation. The regioisomeric glucuronides 12a and 12b have the same mass (m/z 518) as 8, but show a different fragmentation pattern (see supporting information). They were generated starting from hydroxylated metabolites 4 which were additionally glucuronidated. The fragmentation patterns comparable to metabolites 4 allowed the identification of the corresponding metabolites. Furthermore, two metabolites 13 with an additional O-atom were observed, but the fragmentation pattern did not allow the unequivocal assignment of the position of the O-atom. The sulfate 10, which has been identified in the in vitro system after addition of PAPS, was not detected in the urine of the rat. However, whether this metabolite was not formed or was decomposed in the sample urine or during storage remains to be elucidated. Ifenprodil was excreted rapidly during the first period (0–8 h). In this period, ifenprodil is one of the main compounds, together with the glucuronides 7 and 11, assuming comparable ionization factors of all compounds. Glucuronidation was observed as the main metabolic pathway within the first two periods (0–8 h, 8–24 h). The detection of ifenprodil even in the last period of urine collection (24–48 h) indicates the unmodified excretion of ifenprodil even after 24 h (Fig. 8). Metabolic stability of Ifenprodil [5] In in vitro experiments the metabolic stability of ifenprodil in the presence of rat liver microsomes, NADPH/H+ and UDPGA was determined. These co-factors were chosen to generate the main metabolites observed in vivo. For the exact quantification of ifenprodil, a calibration curve was recorded first. Ifenprodil was incubated in different amounts (20, 40, 60, 80 and 100% of the amount used for the incubation with microsomes) with the reaction mixture without NADPH/H+. Additionally, eliprodil was added as internal standard (IS). The ratio ifenprodil/IS was plotted against the employed Ifenprodil amount, which resulted in a good regression coefficient (see supporting information). The ifenprodil concentration in the metabolic active mixture was determined after six periods of incubation up to 120 min. Unexpectedly, incubation with NADPH/H+ and UDPGA resulted in increasing Ifenprodil concentrations after 60 min. This result was explained with fast decomposition of the glucuronide 7, which leads to regeneration of ifenprodil. This theory was confirmed by incubation of ifenprodil only with NADPH/H+ without UDPGA which resulted in continuously decreasing ifenprodil amounts (Fig. 9). After an incubation period of 60 min with both co-factors, 86 ± 2% of ifenprodil remained to be detected. Generation of only phase I metabolites reduced the amount of ifenprodil to 92.8 ± 2% after 60 min. Thus, the main biotransformation of Ifenprodil was caused by glucuronidation reactions. This observation corresponds well with the in vivo experiments, leading to glucuronides 7 and 8 as main metabolites, too. The biotransformation of Ifenprodil, an important lead compound for the development of potent and selective GluN2B selective NMDA receptor antagonists, was analyzed. In in vitro experiments, N-dealkylation, hydroxylation of both aromatic rings and the piperidine moiety were identified as possible reactions. In phase II experiments, glucuronidation of the phenol was observed. Additionally, after incubation with the corresponding co-factors SAM und PAPS, methoxylated and sulfated metabolites were detected. The analysis of a rat urine sample led to the identification of glucuronides, hydroxylated and methoxylated metabolites. The glucuronide 7 was identified as main metabolite. Altogether, the phenol of Ifenprodil is the main structural element susceptible for biotransformation. Especially glucuronidation of the OH group was identified as the main metabolic pathway in vitro and in vivo. These results clearly indicate that the phenol should be replaced bioisosterically in order to obtain metabolically more stable GluN2B selective NMDA receptor antagonists. [5] |
| Toxicity/Toxicokinetics |
mouse LD50 oral 320 mg/kg BEHAVIORAL: ALTERED SLEEP TIME (INCLUDING CHANGE IN RIGHTING REFLEX); BEHAVIORAL: CHANGES IN MOTOR ACTIVITY (SPECIFIC ASSAY) Arzneimittel-Forschung. Drug Research., 21(1992), 1971 [PMID:4400568] The interaction of Ifenprodil with other receptors in the CNS (α1, 5-HT, σ1, σ2 receptor), leads to undesired side effects, e.g. impaired motor function and reduced blood pressure. Nevertheless, ifenprodil serves as an important lead structure for the rational design of novel GluN2B selective antagonists bearing the potential of becoming drugs for life-threatening CNS diseases [5]. |
| References |
[1]. Interactions of erythro-ifenprodil, threo-ifenprodil, erythro-iodoifenprodil, and eliprodil with subtypes of sigma receptors. Eur J Pharmacol. 1995 Feb 6;273(3):307-10. [2]. Antagonist properties of the stereoisomers of ifenprodil at NR1A/NR2A and NR1A/NR2B subtypes of the NMDA receptor expressed in Xenopus oocytes. Eur J Pharmacol. 1996 Jan 25;296(2):209-13. [3]. sigma(2)-receptor ligand-mediated inhibition of inwardly rectifying K(+) channels in the heart. J Pharmacol Exp Ther. 2007 Jul;322(1):341-50. |
| Additional Infomation |
Beart et al. (1991) have reported that or ligands (GBR 12909 and DTG) have no significant effects on erythro-[125I]iodoifenprodil binding to cortical membranes, suggesting that the bulky iodine atom prevents interaction with 0- receptors. However, our data show that erythro-iodoifenprodil binds both subtypes of 0- receptors with moderate affinities, although the introduction of iodine into erythro-ifenprodil decreases affinity for both subtypes of 0- receptors as compared with erythro-ifenprodil. Furthermore, the introduction of an iodine atom does not impair selectivity for 0--2 sites. Therefore, a o- ligand, such as GBR 12909, should be used to mask or receptors if erythro- [tzsI]iodoifenprodil is used for binding assays for polyamine-sensitive sites associated with the NMDA receptors, as reported previously (Hashimoto et al., 1994; Schoemaker et al., 1990). Eliprodil is a less potent ligand for both subtypes of o- receptors than erythro- and threo-diastereomers/threo-ifenprodil of ifenprodil, and the affinity (Ki= 132 nM+26) of eliprodil for 0--1 sites is similar to that (g i = 122 + 13 nM) of erythro-iodoifenprodil. Eliprodil is less potent than the other three compounds at 0--2 sites. In conclusion, it appears that the stereochemistry of ifenprodil may play a significant role in the selectivity for 0"-2 sites. Of the four compounds studied, the threo diastereomer of ifenprodil interacted most preferentially with the 0--2 site, but only with 26-fold greater affinity for the 0--2 versus the 0--1 site. Furthermore, the affinity of the threo diastereomers of ifenprodil and its analogues for al-adrenoceptors is lower than those of the corresponding erythro diastereomers (Chenard et al., 1991). This feature of the threo diastereomer of ifenprodil renders it potentially more useful as a selective o--2 ligand. [1] The results of the present study show that all stereoisomers of ifenprodil have a 500-1000-fold selectivity for the NRIA/NR2B versus NR1A/NR2A NMDA receptor. The two erythro-enantiomers were slightly more potent than the two threo-isomers at blocking NMDA-induced currents in NR1A/NR2A receptors (Table 1). In addition, essentially no difference was found when each of the enantiomers of erythro- and of threo-ifenprodil were compared at the NR1A/NR2A receptor combination. However, at the NR1A/NR2B receptor subtype, a 4-fold higher affinity was found for one of the enantiomers of each of the erythro ((+) enantiomer) and threo ((-) enantiomer) pairs. In the case of the erythro pair, for which we studied the racemate (the drug compound) and both enantiomers individually, the IC50 value of the racemate was intermediate between the ICs0's obtained for each enantiomers and closer to the IC50 of the more potent enantiomer ((+) enantiomer) as would be expected from a competitive interaction of both enantiomers with a single receptor site. Our results are only partially in accordance with those previously obtained with the different ifenprodil stereoisomers on glutamate-induced toxicity of cultured hippocampal neurones, a test taken as an index of NMDA receptor antagonism (Chenard et al., 1991). We found, like these authors, a higher potency of the (-) versus (+) threo isomer. However, calculations based on the activities of each individual enantiomer suggest no difference in potency between (___) erythroifenprodil and (+) threo-ifenprodil at NR1A/NR2A and NR1A/NR2B receptors, whereas in the latter study (+) erythro-ifenprodil was found about 5 times less potent than (+) threo-ifenprodil at preventing glutamate-induced hippocampal neuronal death. The discrepancy between our results and the in vitro glutamate neurotoxicity study suggests that blockade by this drug of the NMDA receptor may not be the sole mechanism involved in its neuroprotective effects. Indeed, ifenprodil was shown recently to possess voltage-operated Ca 2+ channel antagonist properties in cultured hippocampal neurons (Church et al., 1994). A similar neuronal Ca 2 + channel antagonism has been also demonstrated for other neuroprotective compounds acting at the NMDA receptor, such as dextromethorphan (Netzer et al., 1993) or eliprodil, an ifenprodil derivative (Avenet et al., 1994; Biton et al., 1994). The stereoselectivity of ifenprodil at these channels is not known and may completely differ from that observed at NMDA receptors. A 4-fold decrease in the affinity for o--1 sites has been reported when the relative stereochemistry of ifenprodil was changed from (_+) erythro to (_+) threo, whereas no difference in affinity was observed at o.-2 sites (Hashimoto and London, 1995). Since our results suggest no difference in the potency of (_+) erythroand (_+) threo-ifenprodil at blocking NR1A/NR2B or NRIA/NR2A receptors, it is likely that stereochemical requirements for the ~r-1 site and for the above NMDA receptor subtypes differ. This lends support to the current view that the NMDA receptor and the o.-1 site are separate molecular entities. In conclusion, all four stereoisomers of ifenprodil display a high selectivity for the NR1A/NR2B versus NRIA/NR2A subtype of the NMDA receptor. At the NR1/NR2B receptor a small but nonetheless significant difference in potency exists between the enantiomers of each erythro and threo pairs. However, because of the similar potencies of (+) erythro- and (-) threo-ifenprodil, on one hand, and the similar potencies of (-) erythro- and (+) threo-ifenprodil, on the other hand, essentially no difference in the potencies of the racemates (_+) erythro- and (_+) threoifenprodil exists at this receptor subtype. [2] The results presented here show that σ2-receptor agonists exhibit cardiac antiarrhythmic effects in a rabbit model of premature ventricular beats and left ventricular tachycardia. This property is due to a prolongation of myocardial repolarization demonstrated in rabbit Purkinje fibers, arguing in favor of class III antiarrhythmic actions. These compounds block the fast component of the delayed rectifier K+ current generated by the human K+ channel HERG in transfected COS-7 cells. [3] |
Solubility Data
| Solubility (In Vitro) | May dissolve in DMSO (in most cases), if not, try other solvents such as H2O, Ethanol, or DMF with a minute amount of products to avoid loss of samples |
| Solubility (In Vivo) |
Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples. Injection Formulations (e.g. IP/IV/IM/SC) Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline) *Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution. Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline) Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil) Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals). Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)] *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. Injection Formulation 5: 2-Hydroxypropyl-β-cyclodextrin : Saline = 50 : 50 (i.e. 500 μL 2-Hydroxypropyl-β-cyclodextrin → 500 μL Saline) Injection Formulation 6: DMSO : PEG300 : castor oil : Saline = 5 : 10 : 20 : 65 (i.e. 50 μL DMSO → 100 μLPEG300 → 200 μL castor oil → 650 μL Saline) Injection Formulation 7: Ethanol : Cremophor : Saline = 10： 10 : 80 (i.e. 100 μL Ethanol → 100 μL Cremophor → 800 μL Saline) Injection Formulation 8: Dissolve in Cremophor/Ethanol (50 : 50), then diluted by Saline Injection Formulation 9: EtOH : Corn oil = 10 : 90 (i.e. 100 μL EtOH → 900 μL Corn oil) Injection Formulation 10: EtOH : PEG300：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL EtOH → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline) Oral Formulations Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium) Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals). Oral Formulation 3: Dissolved in PEG400 Oral Formulation 4: Suspend in 0.2% Carboxymethyl cellulose Oral Formulation 5: Dissolve in 0.25% Tween 80 and 0.5% Carboxymethyl cellulose Oral Formulation 6: Mixing with food powders Note: Please be aware that the above formulations are for reference only. InvivoChem strongly recommends customers to read literature methods/protocols carefully before determining which formulation you should use for in vivo studies, as different compounds have different solubility properties and have to be formulated differently. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.4969 mL | 12.4844 mL | 24.9688 mL | |
| 5 mM | 0.4994 mL | 2.4969 mL | 4.9938 mL | |
| 10 mM | 0.2497 mL | 1.2484 mL | 2.4969 mL |