ADL5859 HCl

Catalog No.S1139

Molecular Weight(MW): 428.95

ADL5859 HCl is a δ-opioid receptor agonist with K_i of 0.8 nM, selectivity against opioid receptor κ, μ, and weak inhibitory activity at the hERG channel. Phase 2.

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10mM/1mL In DMSO	USD 290	In stock
5mg	USD 170	In stock
10mg	USD 320	In stock
50mg	USD 970	In stock
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Cited by 1 Publication

Expert Opin Inv Drugs, 2012, 21(11):1607-18

PubMed: 22839355

1 Customer Review

ADL-5859 respectively ADL-5747 were dopioid agonists (DORs) which were developed as analgesics for post-operative, neuropathic or musculoskeletal pain. They were expected to have superior analgesic potency over the existing ones, due to the different receptor targeted. However their development was stopped due to unconvincing efficacy.

University of Hong Kong. ADL5859 HCl purchased from Selleck.

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Biological Activity

Description

ADL5859 HCl is a δ-opioid receptor agonist with K_i of 0.8 nM, selectivity against opioid receptor κ, μ, and weak inhibitory activity at the hERG channel. Phase 2.

Targets

δ-opioid receptor ^[1]	μ-opioid receptor ^[1]	κ-opioid receptor ^[1]
0.8 nM(Ki)	32 nM(Ki)	37 nM(Ki)

In vitro

ADL5859 agonizes δ-opioid receptor with a 1000-fold selectivity than µ- or κ-opioid receptor with K_i of 32 nM and 37 nM, respectively.ADL5859 displays weak inhibitory activity at the hERG channel with an IC50 of 78 μM. The EC50 of ADL5859 against δ opioid receptor is 20 nM.^[1]

In vivo

At the screening dose of 3 mg/kg p.o., ADL5859 produces 100% reversal of hyperalgesia in the inflamed paw. The oral ED50 of ADL5859 in the FCA mechanical hyperalgesia assay is 1.4 mg/kg. The antihyperalgesia produced by ADL5859 (3 mg/kg, p.o.) is reversed by pretreatment with the δ opioid antagonist naltrindole (0.3 mg/kg s.c.), thus demonstrating a δ receptor mediated effect.In the rat forced swim assay, ADL5859 (3 mg/kg p.o.) produces robust antidepressant-like activity, as evidenced by a significant decrease in the time spent immobile and a significant increase in the time spent swimming. The bioavailability of ADL5859 (3 mg/kg p.o.) in rats and dogs is 33% and 66%, respectively.^[1]ADL5859 efficiently reduces inflammatory and neuropathic pain mainly by recruiting δ-opioid receptors expressed by peripheral Nav1.8-expressing neurons.^[2]

Protocol

Cell Research:^[1]	+ Expand Cell lines: Chinese hamster ovary (CHO) cells stably expressing human κ, μ, or δ opioid receptors Concentrations: 0 nM-10 nM Incubation Time: 60 minutes Method: Membrane preparations from Chinese hamster ovary (CHO) cells stably expressing human κ, μ, or δ opioid receptors are prepared. The assay buffer used is composed of 50 mMtris(hydroxymethyl) aminomethaneHCl, pH 7.8, 1.0 mM ethylene glycol bis(β-aminoethyl ether)-N,N,N',N'-tetraacetic acid (EGTA free acid), 5.0 mM MgCl₂ 10 mg/L leupeptin, 10 mg/L pepstatin A, 200 mg/L bacitracin, and 0.5 mg/L aprotinin. After dilution in assay buffer and homogenization in a Polytron homogenizer for 30 seconds, membrane proteins (10-80 μg) in 250 μL of assay buffer are added to mixtures containing ADL5859 and [³H]diprenorphine (0.5-1.0 nM, 25000-50000 dpm) in 250 μL of assay buffer in 96-well deep-well polystyrene titer plates and incubated at room temperature for 60 minutes. Reactions are terminated by vacuum filtration with a Brandel MPXR-96T harvester through GF/B filters that have been pretreated with a solution of 0.5% polyethylenimine and 0.1% bovine serum albumin for at least 1 hour. The filters arewashed four times with 1.0 mL each of ice-cold 50 mM Tris-HCl, pH 7.8, and 30 μL of Microscint-20 is added to each filter. Radioactivity on the filters is determined by scintillation spectrometry in a Packard TopCount. [³H]Diprenorphine with a specific activity of 50 Ci/mmolisused. The K_d values for [³H]diprenorphine binding are 0.33 nM for the κ and μ receptors and 0.26 nM for the δ receptor. Receptor expression levels, determined as Bmax values from Scatchard analyses, are 4400, 4700, and 2100 fmol/mg of protein for the κ, μ, and δ receptors, respectively. Preliminary experiments are performed to show that no specific binding is lost during the wash of the filters, that binding achieved equilibrium within the incubation time and remained at equilibrium for at least an additional 60 minutes, and that binding is linear with regard to protein concentration. Nonspecific binding, determined in the presence of 10 μM unlabeled naloxone, is less than 10% of total binding. Protein is quantified by the method of Bradford. The data from competition experiments are fit by nonlinear regression analysis with the program Prism using the four-parameter equation for one-site competition, and K_i values are subsequently calculated from EC50 values by the Cheng-Prusoff equation. (Only for Reference)
Animal Research:^[2]	+ Expand Animal Models: Nav1.8-cKO mice, CMV-KO mice, C57BL6/J × SV129Pas mice Formulation: 0.5% hydroxypropyl methylcellulose/0.1% Tween 80 Dosages: 10 mg/kg - 300 mg/kg Administration: Administered via p.o. (Only for Reference)

Cell Research:^[1]

+ Expand

Cell lines: Chinese hamster ovary (CHO) cells stably expressing human κ, μ, or δ opioid receptors
Concentrations: 0 nM-10 nM
Incubation Time: 60 minutes
Method: Membrane preparations from Chinese hamster ovary (CHO) cells stably expressing human κ, μ, or δ opioid receptors are prepared. The assay buffer used is composed of 50 mMtris(hydroxymethyl) aminomethaneHCl, pH 7.8, 1.0 mM ethylene glycol bis(β-aminoethyl ether)-N,N,N',N'-tetraacetic acid (EGTA free acid), 5.0 mM MgCl₂ 10 mg/L leupeptin, 10 mg/L pepstatin A, 200 mg/L bacitracin, and 0.5 mg/L aprotinin. After dilution in assay buffer and homogenization in a Polytron homogenizer for 30 seconds, membrane proteins (10-80 μg) in 250 μL of assay buffer are added to mixtures containing ADL5859 and [³H]diprenorphine (0.5-1.0 nM, 25000-50000 dpm) in 250 μL of assay buffer in 96-well deep-well polystyrene titer plates and incubated at room temperature for 60 minutes. Reactions are terminated by vacuum filtration with a Brandel MPXR-96T harvester through GF/B filters that have been pretreated with a solution of 0.5% polyethylenimine and 0.1% bovine serum albumin for at least 1 hour. The filters arewashed four times with 1.0 mL each of ice-cold 50 mM Tris-HCl, pH 7.8, and 30 μL of Microscint-20 is added to each filter. Radioactivity on the filters is determined by scintillation spectrometry in a Packard TopCount. [³H]Diprenorphine with a specific activity of 50 Ci/mmolisused. The K_d values for [³H]diprenorphine binding are 0.33 nM for the κ and μ receptors and 0.26 nM for the δ receptor. Receptor expression levels, determined as Bmax values from Scatchard analyses, are 4400, 4700, and 2100 fmol/mg of protein for the κ, μ, and δ receptors, respectively. Preliminary experiments are performed to show that no specific binding is lost during the wash of the filters, that binding achieved equilibrium within the incubation time and remained at equilibrium for at least an additional 60 minutes, and that binding is linear with regard to protein concentration. Nonspecific binding, determined in the presence of 10 μM unlabeled naloxone, is less than 10% of total binding. Protein is quantified by the method of Bradford. The data from competition experiments are fit by nonlinear regression analysis with the program Prism using the four-parameter equation for one-site competition, and K_i values are subsequently calculated from EC50 values by the Cheng-Prusoff equation.
(Only for Reference)

Animal Research:^[2]

+ Expand

Animal Models: Nav1.8-cKO mice, CMV-KO mice, C57BL6/J × SV129Pas mice
Formulation: 0.5% hydroxypropyl methylcellulose/0.1% Tween 80
Dosages: 10 mg/kg - 300 mg/kg
Administration: Administered via p.o.
(Only for Reference)

References

Solubility (25°C)

In vitro	DMSO	86 mg/mL (200.48 mM)
	Water	5 mg/mL (11.65 mM)
	Ethanol	1 mg/mL (2.33 mM)
In vivo	Add solvents individually and in order: 0.5% hydroxyethyl cellulose+0.1% Tween 80	30 mg/mL

* Please note that Selleck tests the solubility of all compounds in-house, and the actual solubility may differ slightly from published values. This is normal and is due to slight batch-to-batch variations.

Chemical Information Download ADL5859 HCl SDF

Molecular Weight	428.95
Formula	C₂₄H₂₈N₂O₃.HCl
CAS No.	850173-95-4
Storage	3 years -20°C powder
Synonyms	N/A

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Clinical Trial Information (data from http://clinicaltrials.gov, updated on 2017-02-16)

NCT Number	Recruitment	Conditions	Sponsor/Collaborators	Start Date	Phases
NCT00979953	Completed	Osteoarthritis of the Knee	Cubist Pharmaceuticals LLC\|Pfizer	October 2009	Phase 2
NCT00603265	Completed	Peripheral Neuropathy\|Neuropathic Pain	Cubist Pharmaceuticals LLC	November 2007	Phase 2
NCT00626275	Completed	Rheumatoid Arthritis	Cubist Pharmaceuticals LLC	October 2007	Phase 2
NCT00993863	Completed	Acute Pain	Cubist Pharmaceuticals LLC	June 2007	Phase 2

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