JDTic

Ki = 0.3 nM

JDTic is a selective opioid Kappa receptor antagonist.

At least three opioid receptor subtypes, μ, δ, and κ, are responsible for the modulation of a diverse array of biological events from nociception to immune regulation. The baisi of studying this complex receptor system is for the identification of both agonists and antagonists with high degree of receptor subtype selectivity.

In vitro: JDTic demonstrated high affinity for the κ receptor in the binding assay and highly potent and selective κ antagonism in the [35S]GTP-γ-S assay. JDTic showed a 16-fold improvement in its κ receptor Ki value in the functional assay relative to the binding assay. In the [35S]GTP-γ-S functional assay, JDTic demonstrated a 3.4-fold increase in κ antagonist potency relative to the functional assay utilizing guinea pig membranes [1].

In vivo: JDTic was found to be able to dose-dependently block acute nicotineinduced antinociception in the tail-flick but not the hotplate test and did not attenuate morphine's antinociceptive effect significantly in either test. Moreover, JDTic failed to block the expression of nicotine reward as measured by the conditioned place preference model. In contrast, JDTic attenuated the expression of both physical and affective nicotine withdrawal signs in mice[2].

Clinical trial: N/A

References:
[1] Thomas JB,Atkinson RN,Rothman RB,Fix SE,Mascarella SW,Vinson NA,Xu H,Dersch CM,Lu Y,Cantrell BE,Zimmerman DM,Carroll FI.  Identification of the first trans-(3R,4R)- dimethyl-4-(3-hydroxyphenyl)piperidine derivative to possess highly potent and selective opioid kappa receptor antagonist activity. J Med Chem.2001 Aug 16;44(17):2687-90.
[2] Jackson KJ,Carroll FI,Negus SS,Damaj MI.  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.

Pharmacodynamic Relationships between Duration of Action of JDTic-like Kappa-Opioid Receptor Antagonists and Their Brain and Plasma Pharmacokinetics in Rats.[Pubmed:27700049]

ACS Chem Neurosci. 2016 Dec 21;7(12):1737-1745.

JDTic is a potent and selective kappa-opioid receptor (KOR) antagonist that reverses U50,488-induced diuresis in rats. It partitions into brain with a duration of action lasting for weeks. In a search for KOR antagonists that do not accumulate in the brain, we compared single doses of five methylated JDTic analogs (RTI-97, -194, -212, -240, and -241) for reversal of U50,488 diuresis and pharmacokinetic (PK) properties. All six compounds showed potent and selective KOR antagonism in a [(35)S]GTPgammaS binding assay. Plasma half-lives ranged from 24 to 41 h and brain half-lives from 24 to 76 h. JDTic and RTI-194 showed increasing brain to plasma ratios over time, indicating increasing partitioning into brain and a longer duration of action for reversal of diuresis than did RTI-97. RTI-240 did not show significant brain accumulation. RTI-212 showed no substantive difference between brain and plasma levels and was inactive against diuresis. RTI-241, with a lower brain to plasma ratio than JDTic and RTI-194, formed JDTic as a metabolite, which still reduced diuresis after 9 weeks. The fact that the duration of action was correlated with the brain to blood plasma ratios and area under the concentration-time curves suggests that PK properties could help to predict safety and acceptable duration of action for KOR antagonists.

Design, synthesis, and pharmacological evaluation of JDTic analogs to examine the significance of replacement of the 3-hydroxyphenyl group with pyridine or thiophene bioisosteres.[Pubmed:27364611]

Bioorg Med Chem. 2016 Aug 15;24(16):3842-8.

The potent and selective KOR antagonist JDTic was derived from the N-substituted trans-3,4-dimethyl-4-(3-hydroxyphenyl)piperidine class of pure opioid antagonists. In previous studies we reported that compounds that did not have a hydroxyl on the 3-hydroxyphenyl group and did not have methyl groups at the 3- and 4-position of the piperidine ring were still potent and selective KOR antagonists. In this study we report JDTic analogs 2, 3a-b, 4a-b, and 5, where the 3-hydroxyphenyl ring has been replaced by a 2-, 3-, or 4-pyridyl or 3-thienyl group and do not have the 3-methyl or 3,4-dimethyl groups, remain potent and selective KOR antagonists. Of these, (3R)-7-hydroxy-N-(1S)-2-methyl-[4-methyl-4-pyridine-3-yl-carboxamide (3b) had the best overall binding potency and selectivity in a [(35)S]GTPgammaS functional assay, with a Ke=0.18nM at the KOR and 273- and 16,700-fold selectivity for the KOR relative to the MOR and DOR, respectively. Calculated physiochemical properties for 3b suggest that it will cross the blood-brain barrier.

N-[(18)F]-FluoropropylJDTic for kappa-opioid receptor PET imaging: Radiosynthesis, pre-clinical evaluation, and metabolic investigation in comparison with parent JDTic.[Pubmed:27821345]

Nucl Med Biol. 2017 Jan;44:50-61.

INTRODUCTION: To image kappa opioid receptor (KOR) for preclinical studies, N-fluoropropylJDTic 9 derived from the best-established KOR antagonist JDTic, was labeled with fluorine-18. METHODS: Radiosynthesis of [(18)F]9 was achieved according to an automated two-step procedure from [(18)F]-fluoride. Peripheral and cerebral distributions were determined by ex vivo experiments and by PET imaging in mouse. Radiometabolism studies were performed both in vivo in mice and in vitro in mouse and human liver microsomes. Identification of the major metabolic fragmentations was carried out by UPLC-MS analysis of enzymatic cleavage of non-radioactive ligand 9. Microsomal metabolic degradation of parent JDTic was also achieved for comparison. RESULTS: The radiotracer [(18)F]9 was produced after 140+/-5min total synthesis time (2.2+/-0.4% not decay corrected radiochemical yield) with a specific activity of 41-89GBq/mumol (1.1-2.4Ci/mumol). Peripheral and regional brain distributions of [(18)F]9 were consistent with known KOR locations but no significant specific binding in brain was shown. [(18)F]9 presented a typical hepatobiliary and renal elimination, and was rapidly metabolized. The in vivo and in vitro radiometabolic profiles of [(18)F]9 were similar. Piperidine 12 was identified as the major metabolic fragment of the non-radioactive ligand 9. JDTic 7 was found to be much more stable than 9. CONCLUSION: Although the newly proposed radioligand [(18)F]9 was concluded to be not suitable for KOR PET imaging due to the formation of brain penetrating radiometabolites, our findings highlight the metabolic stability of JDTic and may help in the design of novel JDTic derivatives for in vivo applications.

Design, synthesis, and pharmacological evaluation of JDTic analogs to examine the significance of the 3- and 4-methyl substituents.[Pubmed:26342544]

Bioorg Med Chem. 2015 Oct 1;23(19):6379-88.

The design and discovery of JDTic as a potent and selective kappa opioid receptor antagonist used the N-substituted trans-3,4-dimethyl-4-(3-hydroxyphenyl)piperidine pharmacophore as the lead structure. In order to determine if the 3-methyl or 4-methyl groups were necessary in JDTic and JDTic analogs for antagonistic activity, compounds 4a-c, and 4d-f which have either the 3-methyl or both the 3- and 4-methyl groups removed, respectively, from JDTic and analogs were synthesized and evaluated for their in vitro opioid receptor antagonist activities using a [(35)S]GTPgammaS binding assay. Other ADME properties were also assessed for selected compounds. These studies demonstrated that neither the 3-methyl or 3,4-dimethyl groups present in JDTic and analogs are required to produce potent and selective kappa opioid receptor antagonists.