title: The macrocyclic tetrapeptide [D-Trp]CJ-15,208 produces short-acting κ opioid receptor antagonism in the CNS after oral administration.
abstract: OBJECTIVE
  Cyclic peptides are resistant to proteolytic cleavage, therefore potentially exhibiting activity after systemic administration. We hypothesized that the macrocyclic κ opioid receptor (KOR)-selective antagonist [D-Trp]CJ-15,208 would demonstrate antagonist activity after systemic, that is, s.c. and oral (per os, p. o.), administration.
  
  
  METHODS
  C57BL/6J mice were pretreated with [D-Trp]CJ-15,208 s.c. or p.o. before administration of the KOR-selective agonist U50,488 and the determination of antinociception in the warm-water tail-withdrawal assay. The locomotor activity of mice treated with [D-Trp]CJ-15,208 was determined by rotorod testing. Additional mice demonstrating cocaine conditioned place preference and subsequent extinction were pretreated daily with vehicle or [D-Trp]CJ-15,208 and then exposed to repeated forced swim stress or a single additional session of cocaine place conditioning before redetermining place preference.
  
  
  RESULTS
  Pretreatment with [D-Trp]CJ-15,208 administered s.c. or p.o. dose-dependently antagonized the antinociception induced by i.p. administration of U50,488 in mice tested in the warm-water tail-withdrawal assay for less than 12 and 6 h respectively. [D-Trp]CJ-15,208 also produced limited (<25%), short-duration antinociception mediated through KOR agonism. Orally administered [D-Trp]CJ-15,208 dose-dependently antagonized centrally administered U50,488-induced antinociception, and prevented stress-, but not cocaine-induced, reinstatement of extinguished cocaine-seeking behaviour, consistent with its KOR antagonist activity, without affecting locomotor activity.
  
  
  CONCLUSIONS
  The macrocyclic tetrapeptide [D-Trp]CJ-15,208 is a short-duration KOR antagonist with weak KOR agonist activity that is active after oral administration and demonstrates blood-brain barrier permeability. These data validate the use of systemically active peptides such as [D-Trp]CJ-15,208 as potentially useful therapeutics.
authors: Torrey Pines Institute for Molecular Studies, Port St. Lucie, FL, USA.
authors: Shainnel O
authors: SO
authors: Eans
authors: Michelle L
authors: ML
authors: Ganno
authors: Kate J
authors: KJ
authors: Reilley
authors: Kshitij A
authors: KA
authors: Patkar
authors: Sanjeewa N
authors: SN
authors: Senadheera
authors: Jane V
authors: JV
authors: Aldrich
authors: Jay P
authors: JP
authors: McLaughlin
mesh_terms: D019900:3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer / Q000494:pharmacology; D000284:Administration, Oral; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D001812:Blood-Brain Barrier / Q000378:metabolism; D003042:Cocaine / Q000008:administration & dosage; D003213:Conditioning, Psychological / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D058999:Drug-Seeking Behavior / Q000187:drug effects; D005108:Extinction, Psychological / Q000187:drug effects; D007279:Injections, Subcutaneous; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009043:Motor Activity / Q000187:drug effects; D010456:Peptides, Cyclic / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D017473:Receptors, Opioid, kappa / Q000037:antagonists & inhibitors*; D013997:Time Factors; D014018:Tissue Distribution
chemical_list: C540936:CJ 15,208; D010456:Peptides, Cyclic; D017473:Receptors, Opioid, kappa; D019900:3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; D003042:Cocaine