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

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

Bioorganic & medicinal chemistry letters (2003-12-04)
Masaaki Hirose, Shin-ichiro Egashira, Yasuhiro Goto, Takashi Hashihayata, Norikazu Ohtake, Hisashi Iwaasa, Mikiko Hata, Takehiro Fukami, Akio Kanatani, Koji Yamada
PMID14643355
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.