The effects of AP521, a novel anxiolytic drug, in three anxiety models and on serotonergic neural transmission in rats

  • J Pharmacol Sci. 2015 Jan;127(1):109-16. doi: 10.1016/j.jphs.2014.11.008.
Ken-Ichi Kasahara  1 ,  Shinji Hashimoto  2 ,  Tsuyoshi Hattori  3 ,  Koh Kawasaki  2 ,  Ryuichi Tsujita  3 ,  Osamu Nakazono  4 ,  Katsuyuki Takao  5 ,  Hiromu Kawakubo  6 ,  Tadashi Nagatani  7
Affiliations
  • 1. Laboratory for Pharmacology, Research Center, Asahi Kasei Pharma Corporation, 632-1 Mifuku, Izunokuni-shi, Shizuoka 410-2321, Japan. Electronic address: [email protected].
  • 2. Focal Product Search & Evaluation, 1-105 Kanda Jinbocho, Chiyoda-ku, Tokyo 101-8101, Japan.
  • 3. Medical Affairs Department, 1-105 Kanda Jinbocho, Chiyoda-ku, Tokyo 101-8101, Japan.
  • 4. Laboratory for Safety Assessment and ADME, Research Center, Asahi Kasei Pharma Corporation, 632-1 Mifuku, Izunokuni-shi, Shizuoka 410-2321, Japan.
  • 5. Clinical Development, Clinical Development Center, 1-105 Kanda Jinbocho, Chiyoda-ku, Tokyo 101-8101, Japan.
  • 6. Nihon Pharmaceutical University, 10281 Komuro Inamachi, Kitaadachi-gun, Saitama 362-0806, Japan.
  • 7. Asahi Kasei Pharma Corporation, 1-105 Kanda Jinbocho, Chiyoda-ku, Tokyo 101-8101, Japan.
PMID: 25704026 DOI: 10.1016/j.jphs.2014.11.008
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.

Keywords
5-HT(1A) receptor; Anxiety; Conditioned fear stress test; Conflict test; Elevated plus maze test.
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