JDTic

From Wikipedia, the free encyclopedia
Jump to: navigation, search
JDTic
JDTic2DCSD2.svg
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 361444-66-8 YesY
ATC code ?
PubChem CID 9956146
ChemSpider 8131755
Synonyms JDTic
Chemical data
Formula C28H39N3O3 
Mol. mass 465.626 g/mol
 YesY (what is this?)  (verify)

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[edit]

References[edit]

  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. ^ 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. 
  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. doi:10.1021/jm701344b. PMID 18307295. 
  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. doi:10.1016/j.ejphar.2004.08.028. PMID 15464069. 
  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. doi:10.1074/jbc.M705540200. PMC 2096775. PMID 17702750. 
  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. doi:10.1124/jpet.107.127415. PMID 17823306. 
  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. doi:10.1007/s00213-005-0167-4. PMID 16184376. 
  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. doi:10.1016/j.ejphar.2005.09.013. PMID 16236279. 
  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. doi:10.1038/nature10939. PMC 3356457. PMID 22437504. 
  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. doi:10.1016/j.bmcl.2014.03.040. PMID 24690494. 
  11. ^ Swearingen, Daniel. "First in Humans Study of JDTic". Retrieved 8 September 2012. 
  12. ^ "Kappa Therapeutics 2013".