title: The novel δ opioid receptor agonist KNT-127 produces antidepressant-like and antinociceptive effects in mice without producing convulsions.
abstract: We previously reported that the δ opioid receptor (DOP) agonists SNC80 and TAN-67 produce potent antidepressant-like and antinociceptive effects in rodents. However, SNC80 produced convulsive effects. Recently, we succeeded in synthesizing a novel DOP agonist called KNT-127. The present study examined the convulsive, antidepressant-like, and antinociceptive effects of KNT-127 in mice. In contrast to SNC80, KNT-127 produced no convulsions at doses of up to 100mg/kg. In mice subjected to the forced swim test, a screening model for antidepressants, KNT-127 (1mg/kg, s.c.) significantly decreased the duration of immobility and increased the duration of swimming without influencing spontaneous locomotor activity. These behavioral changes were similar to that observed for the tricyclic antidepressant imipramine (6mg/kg). The antidepressant-like effect of KNT-127 in mice was antagonized by pretreatment with naltrindole (NTI), a selective DOP antagonist, or naltriben, a putative DOP(2) subtype antagonist. In addition, KNT-127 (3mg/kg, s.c.) significantly reduced the number of acetic acid-induced abdominal constrictions and the duration of licking time, respectively, in mice subjected to a writhing test and a formalin test. These antinociceptive effects were antagonized by pretreatment with either NTI or 7-benzylidenenaltrexone, a putative DOP(1) subtype antagonist. We propose that KNT-127 should be considered as a candidate compound for the development of DOP-based antidepressants and/or analgesics that lack convulsive effects.
authors.affiliation: Department of Neuropsychopharmacology, National Institute of Mental Health, National Center of Neurology and Psychiatry, Tokyo 187-8553, Japan. asaitoh@ncnp.go.jp
authors.forename: Akiyoshi
authors.initials: A
authors.lastname: Saitoh
authors.forename: Azusa
authors.initials: A
authors.lastname: Sugiyama
authors.forename: Toru
authors.initials: T
authors.lastname: Nemoto
authors.forename: Hideaki
authors.initials: H
authors.lastname: Fujii
authors.forename: Keiji
authors.initials: K
authors.lastname: Wada
authors.forename: Jun-Ichiro
authors.initials: J
authors.lastname: Oka
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Nagase
authors.forename: Mitsuhiko
authors.initials: M
authors.lastname: Yamada
mesh_terms: D000700:Analgesics; D000818:Animals; D000928:Antidepressive Agents; D000929:Antidepressive Agents, Tricyclic / Q000494:pharmacology; D001522:Behavior, Animal / Q000187:drug effects; D001549:Benzamides / Q000494:pharmacology; D003863:Depression / Q000517:prevention & control / Q000523:psychology; D018492:Dopamine Antagonists / Q000494:pharmacology; D007099:Imipramine / Q000494:pharmacology; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D009019:Morphinans / Q000494:pharmacology*; D009043:Motor Activity / Q000187:drug effects; D009271:Naltrexone / Q000031:analogs & derivatives / Q000494:pharmacology; D009292:Narcotic Antagonists / Q000494:pharmacology; D010147:Pain Measurement / Q000187:drug effects; D010879:Piperazines / Q000494:pharmacology; D017465:Receptors, Opioid, delta / Q000819:agonists*; D012640:Seizures / Q000139:chemically induced*; D013550:Swimming / Q000523:psychology
chemical_list: D000700:Analgesics; D000928:Antidepressive Agents; D000929:Antidepressive Agents, Tricyclic; D001549:Benzamides; D018492:Dopamine Antagonists; C555233:KNT 127; D009019:Morphinans; D009292:Narcotic Antagonists; D010879:Piperazines; D017465:Receptors, Opioid, delta; C068868:naltrindole benzofuran; C088464:4-(alpha-(4-allyl-2,5-dimethyl-1-piperazinyl)-3-methoxybenzyl)-N,N-diethylbenzamide; D009271:Naltrexone; C055382:naltrindole; D007099:Imipramine