JDTic

JDTic is a selective, long-acting ("inactivating") antagonist of the κ-opioid receptor (KOR).[1][2] JDTic is a 4-phenylpiperidine derivative, distantly related structurally to analgesics such as pethidine and ketobemidone, and more closely to the MOR antagonist alvimopan. In addition, it is structurally distinct from other KOR antagonists such as norbinaltorphimine.[3][4] JDTic has been used to create crystal structures of KOR [ PDB: 4DJH, 6VI4​].[5][6]

JDTic
Clinical data
Other namesJDTic
Identifiers
IUPAC name
  • (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
CAS Number
PubChem CID
IUPHAR/BPS
ChemSpider
UNII
PDB ligand
CompTox Dashboard (EPA)
Chemical and physical data
FormulaC28H39N3O3
Molar mass465.638 g·mol−1
3D model (JSmol)
SMILES
  • 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
InChI
  • InChI=1S/C28H39N3O3/c1-18(2)26(30-27(34)25-13-20-8-9-24(33)12-21(20)15-29-25)17-31-11-10-28(4,19(3)16-31)22-6-5-7-23(32)14-22/h5-9,12,14,18-19,25-26,29,32-33H,10-11,13,15-17H2,1-4H3,(H,30,34)/t19-,25+,26+,28+/m0/s1 N
  • Key:ZLVXBBHTMQJRSX-VMGNSXQWSA-N N
 NY (what is this?)  (verify)

Pharmacology

JDTic is a long-acting ("inactivating") antagonist of the KOR, and is reported to be highly selective for the KOR over the μ-opioid receptor (MOR), δ-opioid receptor (DOR), and nociceptin receptor (NOP).[1][2] However, in another study, JDTic showed little selectivity over the μ-opioid receptor,[7] though it failed to block the effects of the selective μ-opioid receptor agonist sufentanil across a wide range of doses in animals.[8] It has a very long duration of action, with effects in animals seen for up to several weeks after administration of a single dose,[9] although its binding to the KOR is not technically "irreversible" and its long-acting effects are instead caused by altered activity of c-Jun N-terminal kinases.[10]

Animal studies suggest that JDTic may produce antidepressant, anxiolytic, and anti-stress effects,[11] as well as having possible application in the treatment of addiction to cocaine and morphine.[12][13] JDTic shows robust activity in animal models of depression, anxiety, stress-induced cocaine relapse, and nicotine withdrawal.[14]

Discontinuation of clinical development

During phase I human clinical trials for the treatment of cocaine abuse, development of JDTic was halted due to the occurrence of non-sustained ventricular tachycardia,[14] a type of arrhythmia that can potentially be life-threatening. In addition, JDTic showed an unfavorable brain-to-plasma concentration ratio, indicating poor central nervous system penetration.[14][15][16] As a result, new KOR antagonists with more favorable drug profiles (e.g., short-acting, improved brain penetration, etc.), such as ALKS-5461 (a combination of buprenorphine and samidorphan) and CERC-501 (formerly LY-2456302), are being developed instead.[14]

The discontinuation of the clinical development of JDTic is detailed in the following important literature quote:[17]

Overall, the adverse events attributed to JDtic were similar to those reported with placebo, except for cardiac events, such as bradycardia and ventricular tachycardia (VT), which were seen only in the JDTic group. The episodes of VT occurred in two subjects, were not sustained (NSVT), and were asymptomatic. Preclinical experiments in monkeys showed that JDTic administration resulted in a short run of NSVT. Other safety measurements, including clinical laboratory studies, 12-lead ECG, psychomotor function, and measures of mood, did not differ between group during admission or at follow-up. Overall, these results indicate that JDTic administration is associated with short lived, but detectable ventricular tachycardia in 2/6 subjects receiving the active dose. The episodes of NSVT were asymptomatic, were not seen in the majority of subjects, and sporadic. NSVT is known to occur in the general population, although at a low rate. Nonetheless, the likelihood that these cardiac events were induced by JDTic is high, given that both events occurred as a similar time following dosing, the lower incidence of sporadic VT expected in healthy subjects, and the presence of kappa receptors and dynorphin in cardiac tissue. Given the potentially serious clinical consequences of VT and concerns that individuals with cardiovascular disease may have heightened vulnerability, the decision was made by the safety board of this study that further human trials of this drug would not be ethically justified.

In the same paper, LY-2456302 (now CERC-501) was described, "The LY2456302 compound developed by Eli Lilly is an example of a KOR antagonist that does not strongly activate JNK. In a recent phase 1 trial of LY2456302, the authors concluded that the drug was well-tolerated with no clinically significant findings (Lowe et al, 2014)."[17] Note that KOR antagonists that strongly activate JNK are inactivating (long-acting) while those that do not are non-inactivating (short-acting), and that inactivating KOR antagonists are more "complete" and hence potentially more risky inhibitors of the KOR than are non-inactivating antagonists.[17]

See also

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 (2001). "Identification of the First trans-(3R,4R)-Dimethyl-4-(3-hydroxyphenyl)piperidine Derivative to Possess Highly Potent and Selective Opioid κ Receptor Antagonist Activity". Journal of Medicinal Chemistry. 44 (17): 2687–2690. doi:10.1021/jm015521r. PMID 11495579.
  2. Zaveri NT, Journigan VB, Polgar WE (2015). "Discovery of the First Small-Molecule Opioid Pan Antagonist with Nanomolar Affinity at Mu, Delta, Kappa, and Nociceptin Opioid Receptors". ACS Chem Neurosci. 6 (4): 646–57. doi:10.1021/cn500367b. PMC 4401318. PMID 25635572.
  3. Thomas JB, Atkinson RN, Vinson NA, Catanzaro JL, Perretta CL, Fix SE, Mascarella SW, Rothman RB, Xu H, Dersch CM, Cantrell BE, Zimmerman DM, Carroll FI (2003). "Identification of (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-isoquinolinecarboxamide as a Novel Potent and Selective Opioid κ Receptor Antagonist". Journal of Medicinal Chemistry. 46 (14): 3127–3137. doi:10.1021/jm030094y. PMID 12825951.
  4. Cai TB, Zou Z, Thomas JB, Brieaddy L, Navarro HA, Carroll FI (2008). "Synthesis and in vitro Opioid Receptor Functional Antagonism of Analogues of the Selective κ 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-isoquinolinecarboxamide (JDTic)". Journal of Medicinal Chemistry. 51 (6): 1849–1860. doi:10.1021/jm701344b. PMID 18307295.
  5. Wu H, Wacker D, Mileni M, Katritch V, Han GW, Vardy E, Liu W, Thompson AA, Huang XP, Carroll FI, Mascarella SW, Westkaemper RB, Mosier PD, Roth BL, Cherezov V, Stevens RC (2012). "Structure of the Human κ-Opioid Receptor in Complex with JDTic". Nature. 485 (7398): 327–332. Bibcode:2012Natur.485..327W. doi:10.1038/nature10939. PMC 3356457. PMID 22437504.
  6. Che T, English J, Krumm BE, Kim K, Pardon E, Olsen RH, et al. (March 2020). "Nanobody-enabled monitoring of kappa opioid receptor states". Nature Communications. 11 (1): 1145. Bibcode:2020NatCo..11.1145C. doi:10.1038/s41467-020-14889-7. PMC 7052193. PMID 32123179.
  7. Casal-Dominguez JJ, Furkert D, Ostovar M, Teintang L, Clark MJ, Traynor JR, Husbands SM, Bailey SJ (March 2014). "Characterization of BU09059: a novel potent selective κ-receptor antagonist". ACS Chem Neurosci. 5 (3): 177–84. doi:10.1021/cn4001507. PMC 3963132. PMID 24410326.
  8. Carroll I, Thomas JB, Dykstra LA, Granger AL, Allen RM, Howard JL, Pollard GT, Aceto MD, Harris LS (October 2004). "Pharmacological properties of JDTic: a novel kappa-opioid receptor antagonist". Eur J Pharmacol. 501 (1–3): 111–9. doi:10.1016/j.ejphar.2004.08.028. PMID 15464069.
  9. Carroll FI, Thomas JB, Dykstra LA, Granger AL, Allen RM, Howard JL, Pollard GT, Aceto MD, Harris LS (2004). "Pharmacological Properties of JDTic: A Novel κ-Opioid Receptor Antagonist". European Journal of Pharmacology. 501 (1–3): 111–119. doi:10.1016/j.ejphar.2004.08.028. PMID 15464069.
  10. Bruchas MR, Yang T, Schreiber S, Defino M, Kwan SC, Li S, Chavkin C (2007). "Long-Acting κ Opioid Antagonists Disrupt Receptor Signaling and Produce Noncompetitive Effects by Activating c-Jun N-terminal Kinase". Journal of Biological Chemistry. 282 (41): 29803–29811. doi:10.1074/jbc.M705540200. PMC 2096775. PMID 17702750.
  11. Knoll AT, Meloni EG, Thomas JB, Carroll FI, Carlezon WA Jr (2007). "Anxiolytic-Like Effects of κ-Opioid Receptor Antagonists in Models of Unlearned and Learned Fear in Rats". Journal of Pharmacology and Experimental Therapeutics. 323 (3): 838–845. doi:10.1124/jpet.107.127415. PMID 17823306. S2CID 28128824.
  12. Beardsley PM, Howard JL, Shelton KL, Carroll FI (2005). "Differential Effects of the Novel κ Opioid Receptor Antagonist, JDTic, on Reinstatement of Cocaine-Seeking Induced by Footshock Stressors vs Cocaine Primes and its Antidepressant-Like Effects in Rats". Psychopharmacology. 183 (1): 118–126. doi:10.1007/s00213-005-0167-4. PMID 16184376. S2CID 31140425.
  13. Carroll FI, Harris LS, Aceto MD (2005). "Effects of JDTic, a Selective κ-Opioid Receptor Antagonist, on the Development and Expression of Physical Dependence on Morphine Using a Rat Continuous-Infusion Model". European Journal of Pharmacology. 524 (1–3): 89–94. doi:10.1016/j.ejphar.2005.09.013. PMID 16236279.
  14. Urbano M, Guerrero M, Rosen H, Roberts E (May 2014). "Antagonists of the kappa opioid receptor". Bioorg. Med. Chem. Lett. 24 (9): 2021–32. doi:10.1016/j.bmcl.2014.03.040. PMID 24690494.
  15. Clinical trial number NCT01431586 for "First in Humans Study of JDTic" at ClinicalTrials.gov
  16. "Kappa Therapeutics 2013" (PDF).
  17. Chavkin C, Martinez D (August 2015). "Kappa Antagonist JDTic in Phase 1 Clinical Trial". Neuropsychopharmacology. 40 (9): 2057–8. doi:10.1038/npp.2015.74. PMC 4613619. PMID 26174493.
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