kappa-opioid receptor/KOR

The racemic combination (±)-U-50488 is composed of (+)-Trans-(1R,2R)-U-50488 and (-)-Trans-(1S,2S)-U-50488.

[1]. The search for the "next" euphoric non-fentanil novel synthetic opioids on the illicit drugs market: current status and horizon scanning. Forensic Toxicol. 2019;37(1):1-16.

U-50488H is a non-peptide κ-opioid receptor agonist that has been shown to stimulate the release of adrenocorticotropic hormone (ACTH) through the release of arginine vasopressin and corticotropin-releasing hormone from the hypothalamus. (From J Pharmacol Exp Ther 1997;280(1):416-21)

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A detailed description of U-50488H was first published in a peer-reviewed article in 1982. It does not cause respiratory depression or addiction, but it does cause sedation, diuresis, and restlessness, the latter two of which are undesirable in pharmaceuticals, and indicates that its action is mediated by κ-opioid receptors. (−)trans-(1S,2S) U-50488 (U-50488H) and (±)trans racemic mixtures are available from specialty chemical suppliers such as Merck, Tocris Bioscience, Axon Medchem, etc., and are widely used as model κ opioid receptor (KOR) agonists in experimental studies. Upjohn was responsible for the discovery and structure-activity relationship analysis of U-50488H and its related compounds, including the important role of stereochemistry in agonist activity, which was succinctly described by chemist Jacob Szmuszkovicz [15] who was in charge of its development. The general structures of N-substituted benzamide and acetamide are shown in Figure 2a. The structural requirements for potent KOR agonists appear to be a combination of the following factors: (1) (−)trans-(1S,2S) configuration; (2) the presence of an N-methyl group on the nitrogen atom at the carbonyl position; and (3) the presence of a methylene (CH2) "spacer group". The modification of the U-50488H structure further illustrates this point, thereby synthesizing two other highly selective KOR agonists with (-)trans-(1S,2S) configurations: U-62066 (spiradoline, 2-(3,4-dichlorophenyl)-N-methyl-N-[(5R,7S,8S)-7-pyrrolidine-1-yl-1-oxaspiro[4.5]decane-8-yl]acetamide) and U-69593 (N-methyl-2-phenyl-N-[(5R,7S,8S)-7-pyrrolidine-1-yl-1-oxaspiro[4.5]decane-8-yl]acetamide), both of which have heterocyclic structures fused with the cyclohexyl group at the R3 position (Figure 2a, Table 1). The properties of U-50488H were compared with those of the hypothetical novel μ-opioid receptor (MOR) agonist U-47109 (3,4-dichloro-N-(2-(dimethylamino)cyclohexyl)benzamide). This study used U-47700 and U-51754 (2-(3,4-dichlorophenyl)-N-[2-(dimethylamino)cyclohexyl]-N-methylacetamide) (Figure 2) to demonstrate the drug's selectivity for the κ-opioid receptor (KOR). The study found that U-47700, with its (+)-trans-(1R,2R) configuration (assuming U-47109 and U-51754 also have the same configuration), exhibited analgesic effects 7.5 times, 8 times, and 3 times greater than morphine, respectively, in analgesic tests (tail flick test, tail pinch test, and hydrochloric acid writhing test). U-50488H, U-51754, and U-47109 were less potent than morphine but still had measurable analgesic effects. Typical MOR-mediated effects (straub tail, arched back, and increased kinetic activity) were observed in mice treated with U-47700, U-51754, and U-47109, but not in mice treated with U-50488H. [1]

C19H27CL3N2O

405.78948

404.119

C, 56.24; H, 6.71; Cl, 26.21; N, 6.90; O, 3.94

67197-96-0

(1R,2R)-U-50488 hydrochloride;109620-49-7;(-)-U-50488 hydrochloride;114528-79-9;(±)-U-50488 hydrate hydrochloride;(+)-U-50488;67198-17-8;(+)-U-50488 hydrochloride;114528-81-3

6918162

White to light yellow solid powder

5.141

1

2

4

25

428

2

CN([C@@H]1CCCC[C@H]1N2CCCC2)C(=O)CC3=CC(=C(C=C3)Cl)Cl.Cl

KGMMGVIYOHGOKQ-UHFFFAOYSA-N

InChI=1S/C19H26Cl2N2O.ClH/c1-22(19(24)13-14-8-9-15(20)16(21)12-14)17-6-2-3-7-18(17)23-10-4-5-11-23/h8-9,12,17-18H,2-7,10-11,13H2,1H31H

2-(3,4-dichlorophenyl)-N-methyl-N-(-2-(pyrrolidin-1-yl)cyclohexyl)acetamide hydrochloride

U-50,488; U 50,488; U50,488; U-50488; U 50488; (+)-U-50488 hydrochloride; 67197-96-0; 114528-81-3; (+/-)-U-50488 hydrochloride; U50488 Hydrochloride; U-50488E; U-50488 hydrochloride; 107902-84-1; U50488; MCV 4133; NIH 9470; U 50488E

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Note: Please store this product in a sealed and protected environment, avoid exposure to moisture.

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

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

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.)