title: Antidepressant-like responses to the combined sigma and 5-HT1A receptor agonist OPC-14523.
abstract: The antidepressant-like activity of a novel compound, OPC-14523, was investigated in comparison with the conventional antidepressants, fluoxetine and imipramine. OPC-14523 bound with nanomolar affinities to sigma receptors (IC(50)=47-56 nM), the 5-HT(1A) receptor (IC(50)=2.3 nM), and the 5-HT transporter (IC(50)=80 nM). OPC-14523 inhibited the in vitro reuptake of 3H-5-HT (IC(50)=27 nM), but it showed very weak inhibitory activity on 3H-NE and 3H-DA reuptake. OPC-14523 did not inhibit MAO A or B activities or muscarinic receptors. A single oral administration of OPC-14523 produced a marked antidepressant-like effect in the forced swimming test (FST) with rats (ED(50)=27 mg/kg) and mice (ED(50)=20mg/kg) without affecting the general locomotor activity. In contrast, fluoxetine and imipramine each required at least four days of repeated dosing to show this activity. The acute activity of OPC-14523 was blocked by pretreatment with the sigma receptor antagonist NE-100 or the selective 5-HT(1A) receptor antagonist WAY-100635. The induction of flat body posture by OPC-14523 was blocked by the selective 5-HT(1A) receptor antagonist NAN-190, and forebrain 5-HT biosynthesis was attenuated by OPC-14523 at behaviorally effective doses. In contrast, OPC-14523, unlike fluoxetine, failed to inhibit 5-HT reuptake at oral doses below 100mg/kg. Thus, the acute antidepressant-like action of OPC-14523 is achieved by the combined stimulation of sigma and 5-HT(1A) receptors without inhibition of 5-HT reuptake in vivo.
authors.affiliation: Research Institute of Pharmacological and Therapeutical Development, Otsuka Pharmaceutical Co., Ltd, 463-10 Kagasuno 771-0192, Kawauchi-cho Tokushima, Japan. k_tottori@research.otsuka.co.jp
authors.forename: K
authors.initials: K
authors.lastname: Tottori
authors.forename: T
authors.initials: T
authors.lastname: Miwa
authors.forename: Y
authors.initials: Y
authors.lastname: Uwahodo
authors.forename: S
authors.initials: S
authors.lastname: Yamada
authors.forename: M
authors.initials: M
authors.lastname: Nakai
authors.forename: Y
authors.initials: Y
authors.lastname: Oshiro
authors.forename: T
authors.initials: T
authors.lastname: Kikuchi
authors.forename: C A
authors.initials: CA
authors.lastname: Altar
mesh_terms: D000818:Animals; D000928:Antidepressive Agents / Q000378:metabolism / Q000494:pharmacology*; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004359:Drug Therapy, Combination; D006168:Guinea Pigs; D007103:Immobilization / Q000502:physiology; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology; D010879:Piperazines / Q000378:metabolism / Q000494:pharmacology*; D015363:Quinolones / Q000378:metabolism / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D011985:Receptors, Serotonin / Q000378:metabolism*; D044263:Receptors, Serotonin, 5-HT1; D017480:Receptors, sigma / Q000819:agonists* / Q000378:metabolism; D017366:Serotonin Receptor Agonists / Q000378:metabolism / Q000494:pharmacology*
chemical_list: C404207:1-(3-(4-(3-chlorophenyl)-1-piperazinyl)propyl)-3,4-dihydro-5-methoxy-2(1H)-quinolinone; D000928:Antidepressive Agents; D010879:Piperazines; D015363:Quinolones; D011985:Receptors, Serotonin; D044263:Receptors, Serotonin, 5-HT1; D017480:Receptors, sigma; D017366:Serotonin Receptor Agonists