title: The effects of AP521, a novel anxiolytic drug, in three anxiety models and on serotonergic neural transmission in rats.
abstract: We investigated the anxiolytic effects and mechanism of action of a new anxiolytic drug, (R)-piperonyl-1,2,3,4-tetrahydro[1]benzothieno[2,3-c]pyridine-3- carboxamide hydrochloride (AP521). AP521 showed equal or more potent anxiolytic-like effects compared with diazepam, a benzodiazepine receptor agonist, or tandospirone, a partial 5-hydroxytryptamine (5-HT)1A receptor agonist, in three rat anxiety models; the Vogel-type conflict test, elevated plus maze test, and conditioned fear stress test. Although AP521 did not bind to the benzodiazepine receptor, it did bind to 5-HT1A, 5-HT1B, 5-HT1D, 5-HT5A and 5-HT7 receptors, and showed agonist activity for the human 5-HT1A receptor expressed in HEK293 cells. Tandospirone, which can stimulate the presynaptic 5-HT1A receptors in the raphe, tended to decrease extracellular 5-HT concentration in the medial prefrontal cortex (mPFC) in rats. In contrast, AP521 increased extracellular 5-HT concentration. In addition, AP521 enhanced the anti-freezing effect of citalopram, a selective serotonin reuptake inhibitor, in the fear conditioning model in rats and enhanced the citalopram-caused increase of the extracellular 5-HT concentration in the mPFC. These results suggest that AP521 exhibits potent anxiolytic effects by acting as a postsynaptic 5-HT1A receptor agonist and by enhancing serotonergic neural transmission in the mPFC by a novel mechanism of action.
authors.affiliation: Laboratory for Pharmacology, Research Center, Asahi Kasei Pharma Corporation, 632-1 Mifuku, Izunokuni-shi, Shizuoka 410-2321, Japan. Electronic address: kasahara.kc@om.asahi-kasei.co.jp.
authors.forename: Ken-Ichi
authors.initials: K
authors.lastname: Kasahara
authors.affiliation: Focal Product Search & Evaluation, 1-105 Kanda Jinbocho, Chiyoda-ku, Tokyo 101-8101, Japan.
authors.forename: Shinji
authors.initials: S
authors.lastname: Hashimoto
authors.affiliation: Medical Affairs Department, 1-105 Kanda Jinbocho, Chiyoda-ku, Tokyo 101-8101, Japan.
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Hattori
authors.affiliation: Focal Product Search & Evaluation, 1-105 Kanda Jinbocho, Chiyoda-ku, Tokyo 101-8101, Japan.
authors.forename: Koh
authors.initials: K
authors.lastname: Kawasaki
authors.affiliation: Medical Affairs Department, 1-105 Kanda Jinbocho, Chiyoda-ku, Tokyo 101-8101, Japan.
authors.forename: Ryuichi
authors.initials: R
authors.lastname: Tsujita
authors.affiliation: Laboratory for Safety Assessment and ADME, Research Center, Asahi Kasei Pharma Corporation, 632-1 Mifuku, Izunokuni-shi, Shizuoka 410-2321, Japan.
authors.forename: Osamu
authors.initials: O
authors.lastname: Nakazono
authors.affiliation: Clinical Development, Clinical Development Center, 1-105 Kanda Jinbocho, Chiyoda-ku, Tokyo 101-8101, Japan.
authors.forename: Katsuyuki
authors.initials: K
authors.lastname: Takao
authors.affiliation: Nihon Pharmaceutical University, 10281 Komuro Inamachi, Kitaadachi-gun, Saitama 362-0806, Japan.
authors.forename: Hiromu
authors.initials: H
authors.lastname: Kawakubo
authors.affiliation: Asahi Kasei Pharma Corporation, 1-105 Kanda Jinbocho, Chiyoda-ku, Tokyo 101-8101, Japan.
authors.forename: Tadashi
authors.initials: T
authors.lastname: Nagatani
mesh_terms: D000818:Animals; D014151:Anti-Anxiety Agents / Q000494:pharmacology* / Q000627:therapeutic use; D001007:Anxiety / Q000188:drug therapy; D002478:Cells, Cultured; D015283:Citalopram / Q000494:pharmacology; D003975:Diazepam / Q000494:pharmacology; D004195:Disease Models, Animal; D004357:Drug Synergism; D006801:Humans; D054833:Isoindoles / Q000494:pharmacology; D008297:Male; D010879:Piperazines / Q000494:pharmacology; D017397:Prefrontal Cortex / Q000187:drug effects / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology* / Q000627:therapeutic use; D011743:Pyrimidines / Q000494:pharmacology; D051381:Rats; D011985:Receptors, Serotonin / Q000378:metabolism; D012701:Serotonin / Q000378:metabolism*; D058825:Serotonin 5-HT1 Receptor Agonists / Q000494:pharmacology; D009435:Synaptic Transmission / Q000187:drug effects*; D013876:Thiophenes / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: D014151:Anti-Anxiety Agents; D054833:Isoindoles; D010879:Piperazines; D011725:Pyridines; D011743:Pyrimidines; D011985:Receptors, Serotonin; D058825:Serotonin 5-HT1 Receptor Agonists; D013876:Thiophenes; C000606702:piperonyl-1,2,3,4-tetrahydro(1)benzothieno(2,3-c)pyridine-3-carboxamide; D015283:Citalopram; C055267:tandospirone; D012701:Serotonin; D003975:Diazepam
keywords: 5-HT(1A) receptor; Anxiety; Conditioned fear stress test; Conflict test; Elevated plus maze test