a short-acting selective kappa opioid receptor antagonist (original) (raw)

Zyklophin, a systemically active selective kappa opioid receptor peptide antagonist with short duration of action
by
Aldrich JV, Patkar KA, McLaughlin JP.
Department of Medicinal Chemistry, University of Kansas,
Lawrence, KS 66045, USA.
jaldrich@ku.edu
Proc Natl Acad Sci U S A. 2009 Oct 27;106(43):18396-401

ABSTRACT

The cyclic peptide zyklophin {[N-benzylTyr(1),cyclo(D-Asp(5),Dap(8))-dynorphin A-(1-11)NH(2), Patkar KA, et al. (2005) J Med Chem 48: 4500-4503} is a selective peptide kappa opioid receptor (KOR) antagonist that shows activity following systemic administration. Systemic (1-3 mg/kg s.c.) as well as central (0.3-3 nmol intracerebroventricular, i.c.v.) administration of this peptide dose-dependently antagonizes the antinociception induced by the selective KOR agonist U50,488 in C57BL/6J mice tested in the 55 degrees C warm water tail withdrawal assay. Zyklophin administration had no effect on morphine- or SNC-80-mediated antinociception, suggesting that zyklophin selectively antagonizes KOR in vivo. Additionally, the antagonism of antinociception induced by centrally (i.c.v.) administered U50,488 following peripheral administration of zyklophin strongly suggests that the peptide crosses the blood-brain barrier to antagonize KOR in the CNS. Most importantly, the antagonist activity of zyklophin (3 mg/kg s.c.) lasts less than 12 h, which contrasts sharply with the exceptionally long duration of antagonism reported for the established small-molecule selective KOR antagonists such as nor-binaltorphimine (nor-BNI) that last weeks after a single administration. Systemically administered zyklophin (3 mg/kg s.c.) also prevented stress-induced reinstatement of cocaine-seeking behavior in a conditioned place preference assay. In conclusion, the peptide zyklophin is a KOR-selective antagonist that exhibits the desired shorter duration of action, and represents a significant advance in the development of KOR-selective antagonists.

JDTic 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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