Pharmacological properties of JDTic:
a novel kappa-opioid receptor antagonist

by
Carroll I, Thomas JB, Dykstra LA, Granger AL,
Allen RM, Howard JL, Pollard GT, Aceto MD, Harris LS.
Organic and Medicinal Chemistry,
Research Triangle Institute,
Research Triangle Park, North Carolina, USA.
fic@rti.org
Eur J Pharmacol. 2004 Oct 6;501(1-3):111-9


ABSTRACT

Biological studies were conducted on (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-isoquinoline-carboxamide (JDTic), the first potent kappa-selective opioid receptor antagonist not derived from an opiate class of compounds. In the mouse tail-flick test, JDTic, administered subcutaneously (s.c.), blocked anticociceptive activity for up to 2 weeks. When JDTic was administered either s.c. or p.o. 24 h before the selective KOP (kappa)-opioid receptor agonist, enadoline, AD(50s) of 4.1 and 27.3, respectively, were obtained. A time-course study of JDTic versus enadoline indicated significant antagonist p.o. activity up to 28 days. In contrast, JDTic, s.c., failed to antagonize the analgesic effects of the selective MOP mu-opioid receptor agonist, sufentanil. In the squirrel monkey shock titration antinociception test, JDTic given intramuscularly (i.m.) shifted the trans-3,4-dichloro-N-methyl-N-(2-[1-pyrrolidinyl] cyclohexyl) benzeneacetamide (U50,488) dose-effect curve to the right. In the U50,488-induced diuresis rat test, JDTic, s.c., suppressed diuretic activity with a greater potency than that of nor-binaltorphimine (nor-BNI). Thus, JDTic is a potent long- and orally acting selective kappa-opioid antagonist.
JDTic
Zyklophin
Stress/dynorphin
Nor-binaltorphimine
Fentanyl and ketamine
Kappa upregulation and addiction
kappa-Opioid withdrawal in planaria
The mesolimbic kappa-opioid system
Kappa opioid agonists make rats depressed
Kappa antagonists as future antidepressants?
Nalbuphine and anti-analgesia in men and women
Stress, dysphoria and the dynorphin kappa-opioid system
Indolomorphinan antagonists of the kappa-opioid receptor
Kappa agonists, antagonists and partial agonists for mood disorders
The kappa receptor antagonist norbinaltorphimine as an antidepressant
JDTic: an antidepressant, anxiolytic kappa-selective opioid receptor antagonist


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