κ-opioid receptor
κ-Opioid receptor (KOR). JDTic is a highly selective KOR antagonist with IC₅₀ of 0.02 nM. It does not affect μ- or δ-opioid receptors. JDTic blocks dynorphin-KOR signaling and is more selective and potent for KOR than other KOR antagonists.

Opioid receptors mediate the actions of endogenous and exogenous opioids on many physiological processes, including the regulation of pain, respiratory drive, mood, and--in the case of κ-opioid receptor (κ-OR)--dysphoria and psychotomimesis. Here we report the crystal structure of the human κ-OR in complex with the selective antagonist JDTic, arranged in parallel dimers, at 2.9 Å resolution. The structure reveals important features of the ligand-binding pocket that contribute to the high affinity and subtype selectivity of JDTic for the human κ-OR. Modelling of other important κ-OR-selective ligands, including the morphinan-derived antagonists norbinaltorphimine and 5'-guanidinonaltrindole, and the diterpene agonist salvinorin A analogue RB-64, reveals both common and distinct features for binding these diverse chemotypes. Analysis of site-directed mutagenesis and ligand structure-activity relationships confirms the interactions observed in the crystal structure, thereby providing a molecular explanation for κ-OR subtype selectivity, and essential insights for the design of compounds with new pharmacological properties targeting the human κ-OR.[5]

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JDTic inhibits KOR with an IC₅₀ of 0.02 nM. It shows high affinity and selectivity for KOR. JDTic does not affect μ- or δ-opioid receptors. The compound blocks dynorphin-KOR signaling and has been characterized as a potent and selective KOR antagonist.

JDTic dihydrochloride (2.5-16 mg/kg, sc) inhibits the analgesic response to nicotine in a dance manner in the tail flick test but not in the hot plate test or sleep assessment in nicotine-injected mice when tested at any dose JDTic diHClide (3 mg/kg, ip) reverses anxiety-like behavior in a model of the hangover anxiety state. JDTic diHClide (10 mg/kg, intraperitoneal injection) lowers alcohol self-anesthesia and has no effect on preventing cue induction [1]. The effects of alcohol-seeking KOR agonists resume and stop at a swing boiling time point within 2 hours [2]. JDTic dihydrochloride (30 mg/kg, ig) greatly exerts the diuretic action of U50,488 conduction in boiling [3].

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JDTic dose-dependently blocked acute nicotine-induced antinociception in the tail-flick but not the hot-plate test and did not significantly attenuate morphine's antinociceptive effect in either the tail-flick or hot-plate test. Furthermore, JDTic (8 and 16 mg/kg, s.c.) failed to block the expression of nicotine reward as measured by the conditioned place preference model. In contrast, JDTic and the KOR antagonist norBNI attenuated the expression of both the physical (somatic signs and hyperalgesia) and affective (anxiety-related behavior and conditioned place aversion) nicotine withdrawal signs. Conclusions: Our findings clearly show that the KOR is involved in mediating the withdrawal aspects of nicotine dependence. The results from this study suggest that blockade of the KOR by selective KOR antagonists may be useful smoking cessation pharmacotherapies.[2]

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The current study assessed the effects of the selective kappa opioid antagonist JDTic on alcohol (EtOH)-seeking behavior, EtOH relapse, and maintenance responding for EtOH. Adult alcohol-preferring (P) rats were trained in 2-lever operant chambers to self-administer 15% EtOH (v/v) on a fixed-ratio 5 (FR-5) and water on a FR-1 schedule of reinforcement during 1-hr sessions. After 10 weeks, rats underwent extinction training for seven sessions. Rats were then maintained in their home cages for 3 weeks without EtOH access. All rats received an injection (s.c.) of 0, 1, 3, or 10 mg/kg JDTic (n=11-14/group) after the first week of the home cage period. Rats were then tested using the Pavlovian Spontaneous Recovery paradigm (PSR; an animal model of alcohol-seeking) for four sessions during which, responses on the EtOH and water levers were recorded but did not produce their respective reinforcer. Following PSR testing rats were returned to their home cages without access to EtOH for one week prior to the start of EtOH relapse testing. To examine EtOH relapse responding, rats were returned to the operant chambers and the EtOH (FR5) and water (FR1) levers were active. Finally, rats were then tested over 17 operant sessions to assess the effects of JDTic on maintenance responding for EtOH. Rats received 0, 1, 3, or 10 mg/kg JDTic (counterbalanced from the initial experiment) 30 minutes prior to the initial maintenance session. JDTic administered 14 and 25 days prior to testing dose-dependently reduced the expression of an EtOH PSR and relapse responding. In contrast, JDTic did not alter EtOH responding under maintenance conditions. Overall, the results of this study indicate that different mechanisms mediate EtOH self-administration under relapse and maintenance conditions and kappa opioid receptors are involved in mediating EtOH-seeking behavior and relapse responding but not on-going EtOH self-administration.[4]

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JDTic prevents stress-induced reinstatement of cocaine-maintained responding and has antidepressant-like effects in animal models. It has anti-depressant, anti-anxiety, and inhibitory effects on cocaine and nicotine relapse. Detailed in vivo efficacy has been reported in addiction and depression models.

KOR binding assay: Membranes from cells expressing human κ-opioid receptors are incubated with varying concentrations of JDTic and a radiolabeled KOR ligand (e.g., [³H]-U69,593) in binding buffer at room temperature for 60-90 min. Nonspecific binding is determined with excess unlabeled ligand. Bound radioactivity is measured by filtration. IC₅₀ or Ki values are calculated.

Functional antagonist assay: Cells expressing KOR are treated with JDTic at varying concentrations and stimulated with a KOR agonist (e.g., dynorphin). KOR-mediated signaling (e.g., cAMP inhibition or GTPγS binding) is measured. The antagonism of agonist-induced signaling is quantified, and IC₅₀ values are calculated.

The objective of this study is to determine the involvement of the KOR in the initial behavioral responses of nicotine, nicotine reward, and nicotine withdrawal using the highly selective KOR antagonist JDTic. JDTic doses of 1, 4, 8, or 16 mg/kg were administered subcutaneously (s.c.) 18 h prior to nicotine treatment.[2]

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Stress-induced reinstatement model: Animals with a history of cocaine self-administration are subjected to stress (e.g., footshock) to induce reinstatement of drug-seeking behavior. JDTic is administered prior to stress exposure. Reinstatement behavior is measured, and the prevention of stress-induced reinstatement is assessed.

JDTic dihydrochloride has a molecular weight of 538.55 g/mol and molecular formula C₂₈H₄₁Cl₂N₃O₃. CAS number is 785835-79-2. The compound is a highly selective KOR antagonist. Comprehensive PK parameters remain to be characterized.

No detailed toxicity data has been published. JDTic is for research use only. Standard laboratory safety practices should be followed when handling this compound. As a KOR antagonist, potential effects on mood and stress responses should be considered.

[1]. Importance of Phenolic Address Groups in Opioid Kappa Receptor Selective Antagonists. Journal of Medicinal Chemistry (2004), 47(4), 1070-1073.

[2]. Effect of the selective kappa-opioid receptor antagonist JDTic on nicotine antinociception, reward, and withdrawal in the mouse. Psychopharmacology (Berl). 2010 Jun;210(2):285-94.

[3]. Effectiveness of analogs of the kappa opioid receptor antagonist (3R)-7-hydroxy-N-((1S)-1-{[(3R,4R)-4-(3-hydroxyphenyl)-3,4-dimethyl-1-piperidinyl]methyl}-2-methylpropyl)-1,2,3,4-tetrahydro-3-isoquinolinec.Psychopharmacology (Berl). 2010 Jun;210(2):189-98

[4]. The long-lasting effects of JDTic, a kappa opioid receptor antagonist, on the expression of ethanol-seeking behavior and the relapse drinking of female alcohol-preferring (P) rats. Pharmacol Bi.

[5]. Structure of the human κ-opioid receptor in complex with JDTic. Nature. 2012 Mar 21;485(7398):327-32.

In vitro characterization and comparison of JDTic, its dehydroxylated analogues, and nor-BNI and its dehydroxylated analogues showed that the affinity and antagonistic activity of the N-substituted 3,4-dimethyl-(3-hydroxyphenyl)piperidine-derived antagonist JDTic were more dependent on its phenolic hydroxyl group, while those of the corresponding naltrexone-derived antagonist nor-BNI were not. The structural flexibility of the former class of compounds relative to the latter class of compounds is considered to be the reason for this difference. [1]

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JDTic dihydrochloride is a highly selective κ-opioid receptor antagonist with an IC₅₀ of 0.02 nM. It does not affect μ- or δ-opioid receptors. JDTic prevents stress-induced reinstatement of cocaine-seeking behavior and has antidepressant-like effects. The compound is a research tool for studying KOR signaling in addiction and depression. No clinical trials or approved上市 status have been reported.

C28H41CL2N3O3

538.554

537.252

C, 62.45; H, 7.67; Cl, 13.16; N, 7.80; O, 8.91

785835-79-2

JDTic;361444-66-8

66576991

White to off-white solid powder

6.263

6

5

6

36

688

4

C[C@H]1CN(CC[C@@]1(C)C2=CC(=CC=C2)O)C[C@H](C(C)C)NC(=O)[C@H]3CC4=C(CN3)C=C(C=C4)O.Cl.Cl

QJNHURYCTCUGHH-AVWZHOAASA-N

QJNHURYCTCUGHH-AVWZHOAASA-N

JDTic dihydrochloride. InChi Key

JDTic dihydrochloride; 785835-79-2; JDTic (dihydrochloride); Jdtic hydrochloride; VR27M77CW3; JDTic 2HCl; (3R)-7-Hydroxy-N-[(2S)-1-[(3R,4R)-4-(3-hydroxyphenyl)-3,4-dimethylpiperidin-1-yl]-3-methylbutan-2-yl]-1,2,3,4-tetrahydroisoquinoline-3-carboxamide dihydrochloride; 785835-79-2 (HCl);

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)

DMSO : ~100 mg/mL (~185.68 mM)
H2O : ~50 mg/mL (~92.84 mM)

Solubility in Formulation 1: 100 mg/mL (185.68 mM) in PBS (add these co-solvents sequentially from left to right, and one by one), clear solution; with sonication.

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