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.

A non-peptide, kappa-opioid receptor agonist which has also been found to stimulate the release of adrenocorticotropin (ADRENOCORTICOTROPIC HORMONE) via the release of hypothalamic arginine vasopressin (ARGININE VASOPRESSIN) and CORTICOTROPIN-RELEASING HORMONE. (From J Pharmacol Exp Ther 1997;280(1):416-21)

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A detailed description of U-50488H was first published in the peer reviewed literature in 1982. It did not cause respiratory depression and was not habit-forming, but was found to cause sedation, diuresis and dysphoria, the latter properties being undesirable in medicinal products and indicative of KOR-mediated effects. The (−) trans-(1S,2S) U-50488 (U-50488H) and the (±) trans-racemic mixture are commercially available as reagents from specialist chemical supply companies (e.g. Merck, Tocris Bioscience, Axon Medchem etc.) and are widely used as model KOR agonists in experimental studies. The discovery and deconvolution of the structure activity relationships of U-50488H, and its related compounds, including the important role of stereochemistry in agonist activity, was elegantly described by the Upjohn chemist responsible for its development, Jacob Szmuszkovicz [15]. The generic structure of the N-substituted benzamides and acetamides is shown in Fig. 2a. The structural requirements for a potent KOR agonist appear to be a combination of the following: (1) a (−) trans-(1S,2S) configuration; (2) the presence of an N-methyl group on the nitrogen adjacent to the carbonyl and (3) the presence of a methylene (CH2) “spacer”. This is further illustrated by the modifications of the U-50488H structure which lead to the synthesis of two further highly selective KOR agonists with a (−) trans-(1S,2S) configuration; U-62066 (spiradoline, 2-(3,4-dichlorophenyl)-N-methyl-N-[(5R,7S,8S)-7-pyrrolidin-1-yl-1-oxaspiro[4.5]decan-8-yl]acetamide) and U-69593 (N-methyl-2-phenyl-N-[(5R,7S,8S)-7-pyrrolidin-1-yl-1-oxaspiro[4.5]decan-8-yl]acetamide) both of which have a heterocyclic ring structure fused to the cyclohexyl moiety in the R3 position (Fig. 2a, Table 1).
The properties of U-50488H were compared to those of the assumed novel mu-opioid (MOR) agonists U-47109 (3,4-dichloro-N-(2-(dimethylamino)cyclohexyl)benzamide), U-47700 and U-51754 (2-(3,4-dichlorophenyl)-N-[2-(dimethylamino)cyclohexyl]-N-methyl-acetamide) (Fig. 2) to demonstrate the drug’s selectivity for the KOR. In this study, U-47700, which has a (+) trans-(1R,2R) configuration (and it is assumed U-47109 and U-51754 also have the same configuration), was found to have 7.5, eight and three times greater analgesic effect than morphine in antinociceptive tests (tail flick, tail pinch and hydrochloric acid writhing respectively). U-50488H, U-51754 and U-47109 were found to be less potent than morphine, but still had measurable analgesic effects. Characteristic MOR mediated effects (Straub tail, arched back, increased locomotor activity) were observed when mice were treated with U-47700, U-51754 and U-47109 but were not observed for 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.)