World Library  
Flag as Inappropriate
Email this Article
 

JDTic

JDTic
Systematic (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
Clinical data
Legal status
?
Identifiers
CAS number  YesY
ATC code ?
PubChem
ChemSpider  N
Synonyms JDTic
Chemical data
Formula C28H39N3O3 
Mol. mass 465.626 g/mol
 N   

JDTic is a long-acting antagonist of the κ-opioid receptor (KOR). It is highly selective for the KOR, and does not significantly affect the μ-opioid receptor (MOR) or the δ-opioid receptor (DOR).[1] 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.[2][3]

JDTic has a very long duration of action, with effects in animals seen for up to several weeks after administration of a single dose,[4] although its binding to the KOR is not irreversible and its long-acting effects are instead caused by altered activity of c-Jun N-terminal kinases.[5] Animal studies suggest that JDTic may produce antidepressant, anxiolytic, and anti-stress effects,[6] as well as having possible application in the treatment of addiction to cocaine and morphine.[7][8]

The high affinity of JDTic for the KOR suggested that it might be a suitable ligand for promoting the crystallization of this receptor for X-ray crystallographic studies. Such experiments were successful and lead to the publication of the first report of a high-resolution structure of an opioid receptor [ PDB 4DJH ].[9]

JDTic shows robust activity in animal models of depression, anxiety, stress-induced cocaine relapse, and nicotine withdrawal. Upon the initiation of phase I human clinical trials for the treatment of cocaine abuse, however, development was halted due to the incidence of non-sustained ventricular tachycardia,[10] 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.[11][12][10] 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 product of buprenorphine and samidorphan) and LY-2456302, are being developed in its place.[10]

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.  
  2. ^ 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.  
  3. ^ 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.  
  4. ^ 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.  
  5. ^ 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" (pdf). Journal of Biological Chemistry 282 (41): 29803–29811.  
  6. ^ 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" (pdf). Journal of Pharmacology and Experimental Therapeutics 323 (3): 838–845.  
  7. ^ 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.  
  8. ^ 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.  
  9. ^ 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.  
  10. ^ a b c Urbano M, Guerrero M, Rosen H, Roberts E (May 2014). "Antagonists of the kappa opioid receptor". Bioorg. Med. Chem. Lett. 24 (9): 2021–32.  
  11. ^ Swearingen, Daniel. "First in Humans Study of JDTic". Retrieved 8 September 2012. 
  12. ^ "Kappa Therapeutics 2013". 



This article was sourced from Creative Commons Attribution-ShareAlike License; additional terms may apply. World Heritage Encyclopedia content is assembled from numerous content providers, Open Access Publishing, and in compliance with The Fair Access to Science and Technology Research Act (FASTR), Wikimedia Foundation, Inc., Public Library of Science, The Encyclopedia of Life, Open Book Publishers (OBP), PubMed, U.S. National Library of Medicine, National Center for Biotechnology Information, U.S. National Library of Medicine, National Institutes of Health (NIH), U.S. Department of Health & Human Services, and USA.gov, which sources content from all federal, state, local, tribal, and territorial government publication portals (.gov, .mil, .edu). Funding for USA.gov and content contributors is made possible from the U.S. Congress, E-Government Act of 2002.
 
Crowd sourced content that is contributed to World Heritage Encyclopedia is peer reviewed and edited by our editorial staff to ensure quality scholarly research articles.
 
By using this site, you agree to the Terms of Use and Privacy Policy. World Heritage Encyclopedia™ is a registered trademark of the World Public Library Association, a non-profit organization.
 


Copyright © World Library Foundation. All rights reserved. eBooks from Project Gutenberg are sponsored by the World Library Foundation,
a 501c(4) Member's Support Non-Profit Organization, and is NOT affiliated with any governmental agency or department.