title: Anti-stress effects of ONO-2952, a novel translocator protein 18 kDa antagonist, in rats.
abstract: Accumulating evidence has shown the pathophysiological significance of the translocator protein 18 kDa (TSPO) in the central nervous system. In this study, we evaluated the beneficial effects of ONO-2952, a novel TSPO antagonist in rat stress models. ONO-2952 potently bound both rat and human TSPO (Ki=0.330-9.30 nmol/L) with high selectivity over other receptors, transporters, ion channels and enzymes. ONO-2952 inhibited both neurosteroid accumulation and noradrenaline release in the brain of rats exposed to acute stress. The inhibitory effect of ONO-2952 on stress-induced noradrenaline release was attenuated by co-treatment with the TSPO agonist CB34 in a dose-dependent manner. ONO-2952, at 0.3 mg/kg or higher, dose-dependently suppressed restraint stress-induced defecation in rats with brain TSPO occupancy of more than 50%. In addition, ONO-2952, at 1 mg/kg or higher, suppressed conditioned fear stress-induced freezing behavior in rats with an efficacy equivalent to that of diazepam, given orally at 3 mg/kg. Results of the passive avoidance learning test revealed that ONO-2952, unlike diazepam, did not affect learning and memory even at doses 10 times higher than its effective doses in the stress models. The present findings indicate that ONO-2952 is a promising candidate for the treatment of stress-related disorders.
authors.affiliation: Discovery Research Laboratories I, ONO Pharmaceutical Co., Ltd, 3-1-1 Sakurai, Shimamoto-cho, Mishima-gun, Osaka, 618-8585, Japan. Electronic address: ka.mitsui@ono.co.jp.
authors.forename: Katsukuni
authors.initials: K
authors.lastname: Mitsui
authors.affiliation: Discovery Research Laboratories I, ONO Pharmaceutical Co., Ltd, 3-1-1 Sakurai, Shimamoto-cho, Mishima-gun, Osaka, 618-8585, Japan. Electronic address: niwa@ono.co.jp.
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Niwa
authors.affiliation: Discovery Research Laboratories I, ONO Pharmaceutical Co., Ltd, 3-1-1 Sakurai, Shimamoto-cho, Mishima-gun, Osaka, 618-8585, Japan. Electronic address: kawahara@ono.co.jp.
authors.forename: Yuji
authors.initials: Y
authors.lastname: Kawahara
authors.affiliation: Discovery Research Laboratories I, ONO Pharmaceutical Co., Ltd, 3-1-1 Sakurai, Shimamoto-cho, Mishima-gun, Osaka, 618-8585, Japan. Electronic address: no.morimoto@ono.co.jp.
authors.forename: Noriko
authors.initials: N
authors.lastname: Morimoto
authors.affiliation: Medicinal Chemistry Research Laboratories, ONO Pharmaceutical Co., Ltd, 3-1-1 Sakurai, Shimamoto-cho, Mishima-gun, Osaka, 618-8585, Japan. Electronic address: k.ohmoto@ono.co.jp.
authors.forename: Kazuyuki
authors.initials: K
authors.lastname: Ohmoto
authors.affiliation: Medicinal Chemistry Research Laboratories, ONO Pharmaceutical Co., Ltd, 3-1-1 Sakurai, Shimamoto-cho, Mishima-gun, Osaka, 618-8585, Japan. Electronic address: m.katou@ono.co.jp.
authors.forename: Masashi
authors.initials: M
authors.lastname: Kato
authors.affiliation: Pharmaceutical Technology Laboratories, ONO Pharmaceutical Co., Ltd, 3-1-1 Sakurai, Shimamoto-cho, Mishima-gun, Osaka, 618-8585, Japan. Electronic address: yamaura@ono.co.jp.
authors.forename: Yoshiyuki
authors.initials: Y
authors.lastname: Yamaura
authors.affiliation: Pharmacokinetic Research Laboratories, ONO Pharmaceutical Co., Ltd, 3-1-1 Sakurai, Shimamoto-cho, Mishima-gun, Osaka, 618-8585, Japan. Electronic address: n.yoshimoto@ono.co.jp.
authors.forename: Naoki
authors.initials: N
authors.lastname: Yoshimoto
authors.affiliation: Pharmacokinetic Research Laboratories, ONO Pharmaceutical Co., Ltd, 3-1-1 Sakurai, Shimamoto-cho, Mishima-gun, Osaka, 618-8585, Japan. Electronic address: suna@ono.co.jp.
authors.forename: Hideaki
authors.initials: H
authors.lastname: Suna
authors.affiliation: Discovery Research Laboratories I, ONO Pharmaceutical Co., Ltd, 3-1-1 Sakurai, Shimamoto-cho, Mishima-gun, Osaka, 618-8585, Japan. Electronic address: s.katsumata@ono.co.jp.
authors.forename: Seishi
authors.initials: S
authors.lastname: Katsumata
mesh_terms: D000679:Amygdala / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D001362:Avoidance Learning / Q000187:drug effects; D002352:Carrier Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D045744:Cell Line, Tumor; D003521:Cyclopropanes / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D046352:Freezing Reaction, Cataleptic / Q000187:drug effects; D006576:Heterocyclic Compounds, 4 or More Rings / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D008297:Male; D011619:Psychotropic Drugs / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D018079:Receptors, GABA / Q000378:metabolism; D011963:Receptors, GABA-A / Q000378:metabolism; D012149:Restraint, Physical; D013315:Stress, Psychological / Q000188:drug therapy* / Q000378:metabolism
chemical_list: D002352:Carrier Proteins; D003521:Cyclopropanes; D006576:Heterocyclic Compounds, 4 or More Rings; C000607300:ONO-2952; D011619:Psychotropic Drugs; D018079:Receptors, GABA; D011963:Receptors, GABA-A; C499229:TSPO protein, human; C069997:Tspo protein, rat
keywords: Neurosteroid; Noradrenaline; ONO-2952; Stress; Translocator protein 18 kDa