| Size | Price | |
|---|---|---|
| 500mg | ||
| 1g | ||
| Other Sizes |
| Targets |
MCHR1/melanin-concentrating hormonereceptor1 (Ki= 2.2 nM; Kd=530 pM)
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|---|---|
| ln Vitro |
The present study describes the optimisation of an autoradiography assay that provides a means to measure the in vitro potency of melanin-concentrating hormone receptor 1 (MCH(1)) antagonists in native tissues and their ex vivo receptor occupancy. Initial localisation studies demonstrated that the MCH(1) receptor radioligand [(125)I]-S36057 bound to rat caudate putamen with specific binding of consistently >60%. In vitro, the MCH(1) receptor antagonists GW3430, SNAP-94847 and 4'-{[1-(cyclopropylmethyl)piperidin-4-ylidene] [5-fluoro-6-(trifluoromethyl)-1H-benzimidazol-2-yl]methyl}biphenyl-3-carbonitrile (referred to as Compound A) exhibited concentration dependent inhibition of the specific binding of [(125)I]-S36057, with a rank order of affinity of SNAP-94847>Compound A>GW3430. [4]
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| ln Vivo |
SNAP 94847 (oral gavage; 20 mg/kg; 14 days) showed a hyperlocomotor response to acute quinpirole [Treatment: F(2,19)=11.31, Treatment × Time: F(34,323) = 4.061], SNAP The effect of 94847 quinpirole-induced activity was significant compared with untreated animals during the entire observation period [2]. SNAP 94847 in drinking water (orally administered; 20 mg/kg; 21 days) significantly increased mobility compared with untreated animals [Treatment: F(3,28) = 8.971; Treatment × Time: F (51,476)=11.50]. It was shown that the SNAP 94847 treatment group significantly increased exercise after 40 minutes, and this effect remained significant at 180 minutes [2]. SNAP 94847 (oral; 10 mg/kg), has good bioavailability (59%), low plasma and blood clearance of 4.2 L/hr/kg and 3.3 L/hr/kg, respectively, and half-life as shown In a PK study, the duration of action in rats was 5.2 hours [3].
Melanin-concentrating hormone (MCH) is a hypothalamic neuropeptide that plays a role in the modulation of food intake and mood. In rodents, the actions of MCH are mediated via the MCHR1 receptor. The goal of this study was to investigate the effects of acute (1 h) and chronic (28 days) p.o. dosing of a novel MCHR1 antagonist, N-[3-(1-{[4-(3,4-difluorophenoxy)-phenyl]methyl}(4-piperidyl))-4-methylphenyl]-2-methylpropanamide (SNAP-94847), in three mouse models predictive of antidepressant/anxiolytic-like activity: novelty suppressed feeding (NSF) in 129S6/SvEvTac mice and light/dark paradigm (L/D) and forced swim test (FST) in BALB/cJ mice. A significant increase in the time spent in the light compartment of the L/D box was observed in response to acute and chronic treatment with SNAP-94847. An anxiolytic/antidepressant-like effect was found in the NSF test after acute and chronic treatment, whereas no effect was observed in the FST. Because neurogenesis in the dentate gyrus has been shown to be a requirement for the effects of antidepressants in the NSF test, we investigated whether neurogenesis was required for the effect of SNAP 94847. We showed that chronic treatment with SNAP 94847 stimulated proliferation of progenitors in the dentate gyrus. The efficacy of SNAP 94847 in the NSF test, however, was unaltered in mice in which neurogenesis was suppressed by X-irradiation. These results indicate that SNAP 94847 has a unique anxiolytic-like profile after both acute and chronic administration and that its mechanism of action is distinct from that of selective serotonin reuptake inhibitors and tricyclic antidepressants. [1] ystemic injections of SNAP 94847 decreased food-reinforced operant responding and MCH-induced reinstatement of food seeking. SNAP-94847 had no effect on pellet-priming-, cue-, or yohimbine-induced reinstatement. Conclusions: Results indicate that MCH1 receptors are involved in food-reinforced operant responding but not in reinstatement induced by acute exposure to high-fat food, food cues, or the stress-like state induced by yohimbine. These results suggest that different mechanisms mediate food-reinforced operant responding and reinstatement of food seeking. [2] |
| Enzyme Assay |
Competition binding studies [4]
Coronal sections at the level of the caudate putamen were used for competition binding studies. Briefly, following pre-incubation, sections were incubated with 50 pM [125I]-S36057 in the presence of a range of concentrations (0.01 nM–10 μM) of MCH1 receptor antagonists (GW3430, SNAP-94847 or Compound A; all dissolved and diluted in 100% DMSO, and added to assay buffer such that final concentration of DMSO was constant at 1% in the assay) for 90 min as previously described. Non-specific binding was defined using 1 μM MCH in each case. |
| Animal Protocol |
Animal/Disease Models: Rat[2]
Doses: 20 mg/kg Route of Administration: Oral; 20 mg/kg; 14 days Experimental Results: demonstrated excessive locomotor response to acute quinpirole. Animal/Disease Models: Rat (PK study) [3] Doses: 10 mg/kg Route of Administration: po (oral gavage); 10 mg/kg Experimental Results: It demonstrated good physical and chemical properties in rats. SNAP-94847 (3, 10, 15, and 30 mg/kg, intraperitoneal (i.p.)) was dissolved in 20% 2-hydroxypropyl-β-cyclodextrin (encapsin) and yohimbine (2 mg/kg, i.p.) was dissolved in sterile water. [2] Experiment 1: Effect of SNAP-94847 on food-reinforced operant responding [2] We initially studied the effect of systemic injections of SNAP-94847 on ongoing food-reinforced responding. For 14 days, the rats (n=12) were given one 3-h training session as described above. We then assessed the effect of SNAP-94847 on lever presses for the pellets in four 3-h tests that were conducted every 48 h. We used a within-subjects experimental design with the factors of SNAP-94847 dose (vehicle, 3, 10, and 30 mg/kg) and session hour (hours 1, 2, and 3). Each rat was injected with vehicle or one of the doses of SNAP 94847, in a counterbalanced order. SNAP 94847 or its vehicle was injected 60 min prior to the test sessions because previous studies have demonstrated that SNAP-94847 doses of up to 30 mg/kg achieve significant brain penetration by 60 min (DGS unpublished data and Chen et al. 2007). Experiment 2: Effect of SNAP-94847 on MCH-induced reinstatement of food seeking [2] To determine the effect of SNAP-94847 on MCH-induced reinstatement of food seeking, we initially assessed the effect of MCH on this reinstatement. Following our experiment on the effect of systemic injections of SNAP 94847 on food-reinforced responding, we implanted the rats with a guide cannula into the lateral ventricle. After a postoperative recovery period of 5 days, the rats were retrained to lever press for the high-fat food pellets for 3 days and the lever pressing response was extinguished in 13 daily extinction sessions. The rats (n=12) were injected with vehicle or MCH (2.5, 5, 10, and 20μg, i.c.v.) in five test sessions, every 48 h, in an ascending order of MCH dose, with extinction sessions on the intervening days. We used a within-subjects experimental design with the factors of MCH dose (vehicle, 2.5, 5, 10, and 20μg) and session hour. In a different group of rats (n=10), we examined the effect of SNAP-94847 (30 mg/kg, i.p.) on MCH-induced (20μg) reinstatement. We used a within-subjects experimental design with the within-subjects factors of pretreatment condition (0 or 30 mg/kg SNAP 94847), MCH dose (0, 20μg), and session hour. On test days that were separated by 24–72 h, each rat was injected systemically with SNAP-94847 (30 mg/kg) or its vehicle 60 min before the test sessions and then injected with MCH or its vehicle 8–12 min before the sessions; the injections of MCH and its vehicle and SNAP 94847 and its vehicle were counterbalanced. Experiment 3: Effect of SNAP SNAP-94847 on yohimbine-, pellet-priming-, and cue-induced reinstatement of food seeking [2] Pellet-priming-induced reinstatement We tested the effect of SNAP-94847 on pellet-priming-induced reinstatement in four 3-h test sessions with two sessions run consecutively and one extinction day between the two sets of tests. During the test sessions, three food pellets were administered noncontingently within the first minute of the session (i.e., one pellet delivered every 20 s). We used a mixed experimental design that included the between-subject factor of SNAP dose (15 or 30 mg/kg, n=10 in each group) and the within-subjects factors of pretreatment condition (0 and SNAP-94847 [15 or 30 mg/kg]), priming condition (pellet, no pellet), and session hour. On test days that were separated by 24–72 h, each rat was injected systemically with the SNAP-94847 vehicle or one of the SNAP-94847 doses (15 or 30 mg/kg) 60 min before the test sessions and then exposed to the priming condition (three pellets or no pellets); the injections of SNAP 94847 and its vehicle and the priming conditions were counterbalanced. Cue-induced reinstatement [2] As mentioned above, during the training phase, each pellet delivery was paired with a tone–light cue (cue); this cue was not presented during the extinction phase after lever pressing. During the tests for reinstatement, lever responding led to contingent presentations of the cue under the fixed-ratio 1 20-s timeout reinforcement schedule. We tested the effect of SNAP-94847 on cue-induced reinstatement in a total of four test sessions with two sessions run consecutively and five extinction days between test sets. We conducted five extinction days between sets of tests in accordance with previous experiments demonstrating that this procedure minimizes habituation to the presentation of conditioned cues (unpublished data and Bossert et al. 2006; Ghitza et al. 2007). We used a mixed design with between-subject factor of SNAP dose (15 or 30 mg/kg, n=8 in the 15 mg/kg group and n=10 in the 30 mg/kg group) and the within-subjects factors of pretreatment condition (0 and SNAP-94847 [15 or 30 mg/kg]), cue (cue, no cue), and session hour. Yohimbine-induced reinstatement [2] We tested the effect of SNAP-94847 on yohimbine-induced reinstatement in four test sessions with two sessions run consecutively and one extinction day between sets of tests. We used a mixed experimental design that included the between-subject factor of SNAP dose (15 or 30 mg/kg, n=12 in the 15 mg/kg group and n=19 in the 30 mg/kg group) and the within-subjects factors of pretreatment condition (0 and SNAP-94847 [15 or 30 mg/kg]), yohimbine dose (0 or 2 mg/kg), and session hour. Ten rats each in the 15- and 30-mg/kg SNAP-94847 dose were rats previously tested for the effect of SNAP 94847 on pellet-priming-induced reinstatement. These rats were given 2 days of extinction prior to tests for yohimbine-induced reinstatement. On the test days that were separated by 24–72 h, each rat was injected systemically with the SNAP 94847 vehicle or one of the SNAP 94847 doses (15 or 30 mg/kg) 60 min before the test sessions and then injected with yohimbine 15 min later (i.e., 45 min prior to the test session); the injections of SNAP 94847 or its vehicle and yohimbine or its vehicle were counterbalanced. |
| References |
|
| Additional Infomation |
Rationale and objectives: The melanin-concentrating hormone 1 (MCH1) receptors play an important role in home-cage food consumption in rodents, but their role in operant high-fat food-reinforced responding or reinstatement of food seeking in animal models is unknown. Here, we used the MCH1 receptor antagonist SNAP 94847 to explore these questions.
Materials and methods: In experiment 1, we trained food-restricted rats (16 g/day of nutritionally balanced rodent diet) to lever press for high-fat (35%) pellets (3-h/day, every other day) for 14 sessions. We then tested the effect of SNAP 94847 (3-30 mg/kg, intraperitoneal (i.p.)) on food-reinforced operant responding. In experiments 2 and 3, we trained rats to lever press for the food pellets (9 to 14 3-h sessions) and subsequently extinguished the food-reinforced lever responding by removing the food (10 to 17 sessions). We then tested the effect of SNAP 94847 on reinstatement of food seeking induced by MCH (20 microg, intracerebroventricular), noncontingent delivery of three pellets during the first minute of the test session (pellet-priming), contingent tone-light cues previously associated with pellet delivery (cue), or the pharmacological stressor yohimbine (2 mg/kg, i.p.). [2]
|
| Molecular Formula |
C29H33CLF2N2O2
|
|---|---|
| Molecular Weight |
478.58
|
| Exact Mass |
514.22
|
| Elemental Analysis |
C, 72.78; H, 6.74; F, 7.94; N, 5.85; O, 6.69
|
| CAS # |
487051-12-7
|
| Related CAS # |
SNAP 94847 hydrochloride;1781934-47-1
|
| PubChem CID |
16756754
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| Appearance |
Typically exists as solid at room temperature
|
| LogP |
8.429
|
| Hydrogen Bond Donor Count |
1
|
| Hydrogen Bond Acceptor Count |
5
|
| Rotatable Bond Count |
7
|
| Heavy Atom Count |
35
|
| Complexity |
661
|
| Defined Atom Stereocenter Count |
0
|
| SMILES |
CC1=C(C=C(C=C1)NC(=O)C(C)C)C2CCN(CC2)CC3=CC=C(C=C3)OC4=CC(=C(C=C4)F)F
|
| InChi Key |
VMLZFUVIKCGATC-UHFFFAOYSA-N
|
| InChi Code |
InChI=1S/C29H32F2N2O2/c1-19(2)29(34)32-23-7-4-20(3)26(16-23)22-12-14-33(15-13-22)18-21-5-8-24(9-6-21)35-25-10-11-27(30)28(31)17-25/h4-11,16-17,19,22H,12-15,18H2,1-3H3,(H,32,34)
|
| Chemical Name |
N-[3-[1-[[4-(3,4-difluorophenoxy)phenyl]methyl]piperidin-4-yl]-4-methylphenyl]-2-methylpropanamide
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| Synonyms |
SNAP-94847; SNAP94847; SNAP-94847; 487051-12-7; SNAP 94847; N-(3-{1-[4-(3,4-DIFLUOROPHENOXY)BENZYL]-4-PIPERIDINYL}-4-METHYLPHENYL)-2-METHYLPROPANAMIDE; CHEMBL242004; N-(3-(1-(4-(3,4-difluorophenoxy)benzyl)piperidin-4-yl)-4-methylphenyl)isobutyramide; N-[3-[1-[[4-(3,4-difluorophenoxy)phenyl]methyl]piperidin-4-yl]-4-methylphenyl]-2-methylpropanamide; SNAP 94847
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| HS Tariff Code |
2934.99.9001
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| 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)
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| 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
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|---|---|
| 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
Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)(e.g. IP/IV/IM/SC) *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). View More
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)] 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). View More
Oral Formulation 3: Dissolved in PEG400 (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.0895 mL | 10.4476 mL | 20.8951 mL | |
| 5 mM | 0.4179 mL | 2.0895 mL | 4.1790 mL | |
| 10 mM | 0.2090 mL | 1.0448 mL | 2.0895 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
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