delta-opioid receptor (IC50 = 0.94 nM); δ Opioid Receptor/DOR

In the present study, whole-cell patch-clamp technique was used to observe the effects of SNC162, a selective agonist of δ-opioid receptors, on L-type Ca(2+) current (I(Ca-L)) and transient outward K(+) current (I(to)) in rat ventricular myocytes. The results showed that SNC162 significantly inhibited I(Ca-L) and I(to) in rat ventricular myocytes. The maximal inhibition rate of I(Ca-L) and I(to) reached (46.13±4.12)% and (36.53±10.57)%, respectively. SNC162 at 1×10(-4) mol/L inhibited the current density of I(Ca-L) from (8.98±0.40) pA/pF to (4.84±0.44) pA/pF (P<0.01, n=5) and inhibited that of I(to) from (18.69±2.42) pA/pF to (11.73±1.67) pA/pF (P<0.01, n=5). Furthermore, the effects of naltrindole, a highly selective antagonist of δ-opioid receptors, on I(Ca-L) and I(to) were also observed. The results showed that naltrindole alone had no effects on I(Ca-L) and I(to), while it abolished the inhibitory effects of SNC162 on I(Ca-L) and I(to). In conclusion, SNC162 concentration-dependently inhibited I(Ca-L) and I(to) in rat ventricular myocytes via activation of the δ-opioid receptors, which may be a fundamental mechanism underlying the antiarrhythmic effect of activating δ-opioid receptors [3].

The diarylpiperazine δ-opioid agonist SNC80 [(+)-4-[(αR)-α-[(2 S,5 R)-2,5-dimethyl-4-(2-propenyl)-1-piperazinyl]-(3-methoxyphenyl)methyl]-N,N-diethylbenzamide] produces convulsions, antidepressant-like effects, and locomotor stimulation in rats. The present study compared the behavioral effects in Sprague-Dawley rats of SNC80 with its two derivatives, SNC86 [(+)-4-[α(R)-α-[(2 S,5 R)-2,5-dimethyl-4-(2-propenyl)-1-piperazinyl]-(3-hydroxyphenyl)methyl]-N,N-diethylbenzamide] and SNC162 [(+)-4-[(αR)-α-[(2 S,5 R)-2,5-dimethyl-4-(2-propenyl)-1-piperazinyl]-(3-phenyl)methyl]-N,N-diethylbenzamide], which differ by one functional group located in the 3-position of the benzylic ring. In behavioral measures, these three compounds demonstrated a rank order of potency and efficacy; SNC86 was the most potent and efficacious followed by SNC80 and then SNC162. In vitro, these compounds stimulated guanosine 5′-O-(3-[35S]thio)triphosphate ([35S]GTPγS) binding in the caudate putamen of coronal brain slices from drug-naive rats as measured by in vitro autoradiography. In [35S]GTPγS binding studies, SNC86 seemed to be a full agonist at the δ-opioid receptor; however, SNC162 demonstrated reduced stimulation compared with SNC86, consistent with partial agonist activity. Although SNC80 was not fully efficacious in [35S]GTPγS autoradiography studies, it produced behavioral effects similar to those observed with SNC86, suggesting that the behavioral effects of SNC80 may be produced by its 3-hydroxy metabolite. [1]

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Mu-opioid receptor agonists such as fentanyl are effective analgesics, but their clinical use is limited by untoward effects. Adjunct medications may improve the effectiveness and/or safety of opioid analgesics. This study compared interactions between fentanyl and either the noncompetitive N-methyl-D-aspartate (NMDA) glutamate receptor antagonist ketamine or the delta-opioid receptor agonist SNC162 [(+)-4-[(alphaR)-alpha-[(2S,5R)-2,5-dimethyl-4-(2-propenyl)-1-piperazinyl]-(3-phenyl)methyl]-N,N-diethylbenzamide] in two behavioral assays in rhesus monkeys. An assay of thermal nociception evaluated tail-withdrawal latencies from water heated to 50 and 54°C. An assay of schedule-controlled responding evaluated response rates maintained under a fixed-ratio 30 schedule of food presentation. Effects of each drug alone and of three mixtures of ketamine +fentanyl (22:1, 65:1, 195:1 ketamine/fentanyl) or SNC162+fentanyl (59:1, 176:1, 528:1 SNC162/fentanyl) were evaluated in each assay. All drugs and mixtures dose-dependently decreased rates of food-maintained responding, and drug proportions in the mixtures were based on relative potencies in this assay. Ketamine and SNC162 were inactive in the assay of thermal antinociception, but fentanyl and all mixtures produced dose-dependent antinociception. Drug interactions were evaluated using dose-addition and dose-ratio analysis. Dose-addition analysis revealed that interactions for all ketamine/fentanyl mixtures were additive in both assays. SNC162/fentanyl interactions were usually additive, but one mixture (176:1) produced synergistic antinociception at 50°C. Dose-ratio analysis indicated that ketamine failed to improve the relative potency of fentanyl to produce antinociception vs. rate suppression, whereas two SNC162/fentanyl mixtures (59:1 and 176:1) increased the relative potency of fentanyl to produce antinociception. These results suggest that delta agonists may produce more selective enhancement than ketamine of mu agonist-induced antinociception [2].

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Fentanyl and SNC162 interactions [2]
Assay of schedule-controlled responding [2]
The average control response rate (± SEM) throughout the study for this group of monkeys was 3.0 (± 0.2) responses/s. Fentanyl and SNC162 produced dose-dependent decreases in response rates, and slopes of the dose-effect curves were not significantly different [slopes (95% confidence limits) were −131.5 (−186.3 to −76.8) for fentanyl and −119.2 (−162.1 to −76.2) for SNC162]. ED50 values are shown in Table 3, and based on relative potencies, three mixtures of SNC162+fentanyl were examined (59:1, 176:1, 528:1 SNC162/fentanyl). Table 3 also shows the ED50 values for each drug in each mixture, and Table 4 shows the predicted Zadd values and the empirically determined Zmix values for each drug mixture as determined by dose-addition analysis. All drug mixtures produced effects that were consistent with additivity. The isobologram for SNC162/fentanyl interactions in the assay of schedule-controlled responding is shown in Figure 1 (lower left panel).

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Assay of thermal nociception [2]
Average baseline tail-withdrawal latencies (±SEM) throughout the study for this group of monkeys were 0.8 ± 0.1 s and 0.7 ± 0.1 s from 50 and 54°C water, respectively. Fentanyl produced a dose-dependent antinociceptive effect at both thermal stimulus intensities, and the ED50 values for fentanyl at the two stimulus intensities are shown in Table 3. SNC162 did not produce antinociception up to the highest doses tested (maximal % MPE was 24±14.4 and 9.7±8.2 after 10 mg/kg at 50 and 54°C, respectively). Table 3 also shows ED50 values for each drug in the three SNC162/fentanyl mixtures, Table 4 shows the predicted Zadd values and empirically determined Zmix values for each drug mixture, and Figure 1 shows the isobolgrams (bottom center and left panels). The ED50 values for fentanyl and SNC162 in the 176:1 mixture were significantly lower than the ED50 values for either drug alone at 50°C (Table 3). Moreover, the 176:1 SNC162/fentanyl mixture produced a synergistic antinociceptive effect at 50°C as indicated by the empirically determined Zmix value being significantly lower than the predicted Zadd value (Table 4). Graphically, this drug-mixture point was located to the left of the dose-additivity line in the isobologram (Fig. 1, bottom center panel). This synergistic effect with the 176:1 SNC162/fentanyl mixture was replicated in a subsequent experiment (data not shown). The 59:1 and 528:1 SNC162/fentanyl mixtures produced only additive effects at a stimulus intensity of 50°C, and all SNC162/fentanyl mixtures produced additive effects at a stimulus intensity of 54°C.

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Dose-ratio analysis [2]
Fig. 2 shows dose ratios for ketamine+fentanyl and SNC162+fentanyl to produce rate suppression in the assay of schedule-controlled responding (SCR) vs. thermal antinociception (50 and 54°C). Ketamine produced only a proportion-dependent decrease in the dose ratios at both stimulus intensities, indicating that antinociceptive doses of the ketamine/fentanyl mixtures produced greater rate suppression than antinociceptive doses of fentanyl alone. Conversely, SNC162 increased the dose ratio relative to fentanyl alone at 50°C (both the 59:1 and 176:1 mixtures) and at 54°C (the 59:1 mixture). Thus, antinociceptive doses of some SNC162/fentanyl mixtures produced less rate suppression than antinociceptive doses of fentanyl alone.

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Time courses [2]
Fig. 3 shows the time courses of equieffective doses of fentanyl (0.021 mg/kg), ketamine (1.4 mg/kg) and SNC162 (3.7 mg/kg) in the assay of schedule-controlled responding. All three drugs produced a significant decrease in response rates relative to saline treatment. Peak effects of all three drugs were observed after 10 min, and effects of all three drugs dissipated after 300 min. Using the duration of significant differences from saline treatment as a criterion, durations of action were ketamine

Biochemicals and solution [3]
SNC162, Taurine, 4-aminopyridine (4-AP), ATP-K2, ATPMg, L-glutamic acid, EGTA, and naltrindole were used. The composition of Ca2+-free Tyrode’s solution (in mmol/ L): NaCl 140, KCl 5.4, MgCl2 1.0, NaH2PO4 0.33, glucose 10, HEPES 5.0, and the pH was adjusted to 7.38 with NaOH at room temperature. The composition of Tyrode’s solution: 1.8 mmol/L CaCl2 was added into Ca2+-free Tyrode’s solution. The composition of enzymatic solution (in mmol/L): 50 mL Tyrode’s solution without CaCl2 1.8, NaCl 140, but with NaCl 125, taurine 20, CaCl2 75 µmol/ L, collagenase P 0.1-0.3 g/L. The composition of KB solution (in mmol/L): KOH 85, L-glutamic acid 50, KCl 30, taurine 20, KH2PO4 30, MgCl2 1.0, HEPES 10, glucose 10 and EGTA 0.5, and the pH was adjusted to 7.4 by KOH. The extracellular solution used for measuring ICa-L was Tyrode’s solution and the composition of the pipette solution was (in mmol/L): KCl 150, HEPES 5.0, EGTA 5.0, ATP-K2 3.0, MgCl2 1.0, 4-AP 5.0, ATP-Mg 1.0, and the pH was adjusted to 7.3 by KOH. The extracellular solution used for measuring Ito was the same as that for measuring ICa-L, except that CdCl2 0.1 mmol/L and BaCl2 0.2 mmol/L were added into the perfusate to avoid ICa-L and inward rectifier potassium current (IK1) participating. The composition of the pipette solution was the same as that for measuring ICa-L except lacking 4-AP. SNC162 was dissolved to 0.01 mol/L with 1 mol/L HCl and stored at -20 o C, then diluted to the desired final concentration before each experiment. Naltrindole was dissolved to 0.01 mol/L with distilled water and stored at -20 oC, then diluted to the desired final concentration before each experiment. In the experiment, each agent was cumulatively administered.

Electrophysiologic recording [3]
ICa-L and Ito were recorded by whole-cell patch-clamp technique. The isolated cells were placed in a recording chamber mounted on the stage of an inverted microscope. After cell settling for 3-5 min, the chamber was continuously perfused with Tyrode’s solution at 1-2 mL/min. The patch electrodes, made from borosilicate glass capillaries, were pulled in two stages by a vertical microelectrode puller ith resistances ranging from 2-5 MΩ when filled with pipette solution. The pipette was connected through an Ag-AgCl wire to the head stage of an Axon 200B amplifier. A three dimensional hydraulic micromanipulator was used to position the patch electrode near the center of the cell. After offset voltage adjustment, a giga seal was established between the electrode tip and the membrane by applying slight negative pressure (10-20 cm H2O). Then the patch membrane was ruptured by a brief period of stronger negative pressure. Data acquisition and analysis were carried out with pClampex 8.2. In all experiments, membrane current density was expressed as membrane current per cell capacitance.

Fentanyl/ketamine interactions were examined in a group of five monkeys, and fentanyl/SNC162 interactions were examined in a different group of three monkeys (two monkeys were included in both studies). Initially, complete dose-effect curves were determined for fentanyl (0.001–0.1 mg/kg) and ketamine (0.1–5.6 mg/kg) alone, or for fentanyl and SNC162 (0.1–10 mg/kg) alone, and each drug was tested twice. Tests of fentanyl and ketamine alone were conducted no more than twice a week. Tests of SNC162 alone were conducted no more than once a week to prevent tolerance to the rate-decreasing effects of this delta agonist (Brandt et al., 2001). Subsequently, three mixtures of ketamine or SNC162 in combination with fentanyl were examined, and the proportions of each drug in the mixtures were based on the relative potency of the drugs to decrease response rates. Thus, relative potency was defined as ED50 of the combination drug (ketamine or SNC162) ÷ ED50 fentanyl, and the proportions of the combination drug to fentanyl in the three mixtures were relative potency ÷ 3, relative potency, and relative potency × 3. Each mixture was tested at least once, and test sessions were conducted no more than twice a week for fentanyl/ketamine mixtures and no more than once a week for fentanyl/SNC162 mixtures. Fentanyl, ketamine, SNC162, and all mixtures were tested up to doses that eliminated responding in most or all monkeys. [2]

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Drug interactions can be influenced not only by the relative doses of two drugs in a mixture, but also by their relative time courses; nominal drug proportions in an administered mixture are most likely to approximate actual biologically available drug proportions if the drugs have similar time courses (e.g. Kenakin, 1987). Accordingly, the relative time courses of fentanyl, ketamine and SNC162 were compared in a group of four monkeys. For these time course experiments, either saline or a single dose of fentanyl, ketamine or SNC162 was administered, and 5 min response periods identical to those described above were initiated 10, 30, 100, and 300 min after administration. The fentanyl dose was determined as the ED90 dose from cumulative dosing experiments described above. Ketamine and SNC162 doses were based on their relative potency to fentanyl.[2]

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Fentanyl/ketamine interactions were examined in a group of three monkeys, and fentanyl/SNC162 interactions were examined in a different group of four monkeys (three monkeys were included in both studies). Initially, complete dose-effect curves were determined for fentanyl (0.001–0.056 mg/kg) and ketamine (0.1–5.6 mg/kg) alone, or for fentanyl and SNC162 (0.1–10 mg/kg) alone. Subsequently, three mixtures of fentanyl in combination with ketamine or SNC162 were examined, and the proportions of each drug in the mixtures were identical to those examined in the assay of schedule-controlled responding described above. Each drug mixture was tested once, and any mixtures producing a synergistic effect were tested a second time to evaluate reliability of results. As in the assay of schedule-controlled responding, test sessions were conducted no more than twice a week, and tests with SNC162 alone or in combination with fentanyl were conducted only once per week. Time courses were not compared in the assay of thermal nociception because fentanyl was the only one of the three drugs that was active in this procedure.[2]

Interaction between fentanyl and SNC162[2] Unlike ketamine, a certain proportion of SNC162 selectively enhances the analgesic effect of fentanyl. These results are consistent with previous studies that have shown that δ receptor agonists can selectively enhance the analgesic effect of μ receptor agonists in rodents and rhesus monkeys via δ receptor-mediated enhancement (Negus et al., 2009; O'Neill et al., 1997; Stevenson et al., 2003; Stevenson et al., 2005). The results of this study extend these earlier findings in two ways. First, this study directly compares the interaction between μ receptor agonists and δ receptor agonists or ketamine. Under the conditions of this study, only δ receptor agonists were able to selectively enhance the analgesic effect induced by μ receptor agonists. Therefore, these results provide evidence that δ/μ receptor interactions may have greater clinical benefits than the more extensively studied and potentially more useful interactions between μ receptor agonists and ketamine. Secondly, this study included SNC162 within the range of known delta receptor agonists that selectively enhance the analgesic effect of μ-opioids in rhesus monkeys. The relatively weak analgesic synergy observed when fentanyl was used in combination with SNC162 may be related to the potency of SNC162 at the delta receptor. We have previously reported that delta receptor agonists require high potency to produce analgesic synergy when combined with μ receptor agonists, while highly potent delta receptor agonists, such as SNC80 and SNC243A, can selectively enhance the analgesic effect of μ receptor agonists under different proportions and intensities of noxious stimuli (Negus et al., 2009; Stevenson et al., 2003; Stevenson et al., 2005). The potency of SNC162 in both in vitro functional and in vivo behavioral studies was lower than that of other delta receptor agonists, such as SNC80 (Jutkiewicz et al., 2004; Negus et al., 1998). Therefore, SNC162 had a weaker enhancing effect on μ-receptor agonist-induced analgesia, consistent with its low potency on δ-receptors.

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Drug action time course as a factor of drug interaction[2]
Time course data in the programmed response assay showed that the duration of action of SNC162 was slightly longer than that of ketamine. However, three findings suggest that time course was not the primary determinant of drug interaction in this study. First, all three drugs reached peak effect within 10 minutes, which is the pretreatment time used in the programmed response and thermal analgesia assays. Therefore, drug interactions in both assays were assessed when all drugs reached peak effect. Second, the cumulative dosing studies used half-log or quarter-log dose escalation. Therefore, any cumulative drug dose was primarily composed of the most recently administered dose, with little contribution from residual drug from previous doses. This suggests that small differences in the duration of action are expected to result in only relatively small changes in the actual proportion of drug over the cumulative dosing process. Finally, although the time course of action of each drug differed when compared to the saline treatment group, there were no significant differences in the time course of action among them. This again demonstrates that the differences in the time course of action were not significant.

[1]. Delta-opioid agonists: differential efficacy and potency of SNC80, its 3-OH (SNC86) and 3-desoxy (SNC162) derivatives in Sprague-Dawley rats. J Pharmacol Exp Ther. 2004 Apr;309(1):173-81.

[2]. Selective enhancement of fentanyl-induced antinociception by the delta agonist SNC162 but not by ketamine in rhesus monkeys: Further evidence supportive of delta agonists as candidate adjuncts to mu opioid analgesics. Pharmacol Biochem Behav. 2010 Aug 3;97(2):205–212.

[3]. Activation of δ-opioid receptors inhibits L-type Ca(2+) current and transient outward K(+) current in rat ventricular myocytes. Sheng Li Xue Bao . 2008 Feb 25;60(1):38-42.

4-[(S)-[(2S,5R)-2,5-dimethyl-4-prop-2-enyl-1-piperazinyl]-phenylmethyl]-N,N-diethylbenzamide is a diarylmethane. In the [35S]GTPγS autoradiography assay, dose-concentration curves were determined using rat striatal sections. Previous studies have shown that GTPγS binding stimulated by δ-opioid receptor agonists is most pronounced in the striatum (Hyytia et al., 1999). SNC86, SNC80, and SNC162 all stimulated [35S]GTPγS binding in rat striatal sections in a dose-dependent manner, with EC50 values (±SEM) of 0.81 (0.11), 67 (2.7), and 33 (2.5) nM, respectively (Figure 2). In addition, SNC86 showed a higher maximum…
The binding of SNC80 and its derivatives to [35S]GTPγS was determined in isolated rat caudate nucleus putamen slices. These studies showed that SNC86 was the most potent and most effective compound. SNC80 and SNC162 produced similar levels of GTPγS stimulation and similar EC50 values (67 nM and 33 nM, respectively). However, in behavioral studies, the potency and efficacy of the three compounds increased sequentially, with SNC86 being the most potent and most effective compound…[1]

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The main finding of this study was that the non-competitive NMDA receptor antagonist ketamine failed to enhance the analgesic effect of fentanyl or improve the relative potency of fentanyl in producing analgesia and heart rate inhibition in rhesus monkeys. Conversely, certain combinations of fentanyl with the δ-opioid receptor agonist SNC162 did produce synergistic analgesia and/or enhanced analgesic potency, thereby strengthening the inhibition of heart rate depression. These results suggest that δ receptor agonists may be more effective as adjunctive therapy to μ receptor agonist analgesics than non-competitive NMDA receptor antagonists in pain management.
Effects of fentanyl, ketamine and SNC162 alone[2]
The effects of fentanyl, ketamine and SNC162 alone are consistent with previous findings. Therefore, the μ-selective opioid analgesic fentanyl has been shown to produce analgesic effects in rodents and non-human primates and is widely recognized as an opioid analgesic for humans (Baker et al., 2002; Dambisya and Lee, 1994; Gatch et al., 1998; Hoffmann et al., 2003b; Nadeson et al., 2002; Negus et al., 2008; Negus et al., 2009; Stevenson et al., 2003; Tucker et al., 2005). Fentanyl also exhibits dose-dependent response inhibition, consistent with previous findings in our laboratory (Negus et al., 2008; Negus et al., 2009; Stevenson et al., 2003). As previously mentioned, SNC162 was ineffective in the tail-retraction test but dose-dependently reduced the programmed response rate (Negus et al., 1998). Similar to SNC162, ketamine failed to alter thermal pain perception in the tail-retraction test but dose-dependently reduced the programmed response rate in rats. These findings are largely consistent with previous reports that ketamine and other non-competitive NMDA antagonists do not alter thermal pain perception in rhesus monkeys (Butelman et al., 2003; Dykstra and Woods, 1986; France et al., 1989; Negus et al., 1993) or other species (Dambisya and Lee, 1994; Hoffmann et al., 2003b; Tucker et al., 2005), even at doses sufficient to eliminate the programmed response rate or produce other significant sedation and motor disturbances. High doses of the sedative ketamine and other non-competitive NMDA receptor antagonists may impair withdrawal responses (Dykstra and Woods, 1986; France et al., 1989), but in this study, tail retraction responses were preserved within the dose range examined, and higher doses were not tested to avoid severe motor dysfunction. This study showed that the δ-opioid receptor agonist SNC162 inhibited ICa-L and Ito in rat ventricular myocytes in a concentration-dependent manner. The study also showed that the selective δ-opioid receptor antagonist naltrexindole alone had no effect on ICa-L and Ito, but it completely eliminated the effect of SNC162 on ICa-L and Ito, suggesting that δ-opioid receptors mediate the inhibitory effect of SNC162 on ICa-L and Ito. Transmembrane Ca2+ influx through L-type Ca2+ channels is a major trigger for excitation-contraction coupling in working myocardium [11]. However, in cases of digitalis poisoning or ischemia-reperfusion, it may also be an important pathway for inducing intracellular Ca2+ overload, leading to delayed post-depolarization (DAD) and triggered arrhythmias [7,12]. Inhibition of ICa-L can reduce transmembrane Ca2+ influx and alleviate intracellular Ca2+ overload. Therefore, the inhibitory effect of SNC162 on ICa-L may contribute to its antiarrhythmic effect by activating δ-opioid receptors. Ito receptors are activated by rapid depolarization associated with INa and are responsible for transient repolarization in phase 1 of the action potential [6]. Itto channels have been reported to prolong the action potential duration (APD) [13] and effective refractory period, which would greatly help eliminate reentry and thus reduce the incidence of arrhythmias or ventricular fibrillation. Some antiarrhythmic drugs, such as flecainide, quinidine, disopyramide, and tedesamide, have been reported to nonselectively inhibit itto channels [14-16]. Currently, ito channel blockers have been used to treat Brugada syndrome[17]. In our experiment, SNC162 inhibited the ito channel, which may be one of the mechanisms by which it exerts its antiarrhythmic effect by activating δ-opioid receptors. δ-opioid receptors have been reported to have two subtypes, δ1 and δ2[18]. However, neither SNC162 nor naltrexindole used in this study exhibits selectivity for either δ1 or δ2 subtypes. Our results indicate that the observed effect is only related to δ-opioid receptors. The effects of selective agonists on δ-opioid receptor subtypes remain to be investigated. In summary, SNC162 inhibits ICa-L and Ito in rat ventricular myocytes in a concentration-dependent manner by activating δ-opioid receptors, which may be the basic mechanism by which it exerts its antiarrhythmic effect by activating δ-opioid receptors.[3]

C27H37N3O

419.60200

419.294

C, 77.28; H, 8.89; N, 10.01; O, 3.81

178803-51-5

6604878

White to off-white solid powder

1.027g/cm3

536.4ºC at 760mmHg

202.4ºC

1.4E-11mmHg at 25°C

1.549

4.714

0

3

8

31

561

3

CCN(CC)C(=O)C1=CC=C(C=C1)[C@H](C2=CC=CC=C2)N3C[C@H](N(C[C@@H]3C)CC=C)C

WGIDFDFAOQVAHY-UFPGJGBJSA-N

InChI=1S/C27H37N3O/c1-6-18-29-19-22(5)30(20-21(29)4)26(23-12-10-9-11-13-23)24-14-16-25(17-15-24)27(31)28(7-2)8-3/h6,9-17,21-22,26H,1,7-8,18-20H2,2-5H3/t21-,22+,26+/m1/s1

4-[(S)-[(2S,5R)-2,5-dimethyl-4-prop-2-enylpiperazin-1-yl]-phenylmethyl]-N,N-diethylbenzamide

SNC162; SNC 162; 178803-51-5; 4-[(S)-[(2S,5R)-2,5-DIMETHYL-4-(2-PROPENYL)-1-PIPERAZINYL]PHENYLMETHYL]-N,N-DIETHYLBENZAMIDE; 4-[(S)-[(2S,5R)-2,5-dimethyl-4-prop-2-enylpiperazin-1-yl]-phenylmethyl]-N,N-diethylbenzamide; 4-[(S)-[(2S,5R)-2,5-dimethyl-4-prop-2-enyl-1-piperazinyl]-phenylmethyl]-N,N-diethylbenzamide; CHEMBL153648;

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 : ~5 mg/mL (~11.92 mM)

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.

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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).

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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)

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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).

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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

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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.

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