N-acyl 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline: the first orexin-2 receptor selective non-peptidic antagonist

  • Bioorg Med Chem Lett. 2003 Dec 15;13(24):4497-9. doi: 10.1016/j.bmcl.2003.08.038.
Masaaki Hirose  1 ,  Shin-ichiro Egashira ,  Yasuhiro Goto ,  Takashi Hashihayata ,  Norikazu Ohtake ,  Hisashi Iwaasa ,  Mikiko Hata ,  Takehiro Fukami ,  Akio Kanatani ,  Koji Yamada
Affiliations
  • 1. Banyu Tsukuba Research Institute, Banyu Pharmaceutical Co., Ltd, Okubo 3, Tsukuba 300-2611, Ibaraki, Japan. [email protected]
PMID: 14643355 DOI: 10.1016/j.bmcl.2003.08.038
Abstract

The identification of potent and selective orexin-2 receptor (OX(2)R) antagonists is described based on the modification of N-acyl 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline analogue 1, recently discovered during high throughput screening (HTS). Substitution of an acyl group in 1 with tert-Leucine (tert-Leu), and introduction of a 4-pyridylmethyl substituent onto the amino function of tert-Leu improved compound potency, selectivity, and water solubility. Thus, compound 29 is a promising tool to investigate the role of orexin-2 receptors.

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