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]
The discontinuation of the clinical development of JDTic is detailed in the following important literature quote:[16]
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)."[16] 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.[16]
^ abThomas 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. PMID11495579.
^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. PMID12825951.
^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. PMID18307295.
^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. PMID15464069.
^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. PMID15464069.
^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. PMID17823306. S2CID28128824.
^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. PMID16184376. S2CID31140425.
^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. PMID16236279.
^ abcUrbano 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. PMID24690494.
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