Bioactivity-guided synthesis of gramine derivatives as new MT₁ and 5-HT_1A receptors agonists

Abstract

Twenty-four gramine derivatives were synthesized and evaluated on MT₁ and 5-HT_1A receptors in vitro. Among them, seven derivatives (7, 8, 16, 19, 20, 21, and 24) exhibited higher agonisting activities on MT₁ or 5-HT_1A receptors. Compared with gramine, derivatives 7, 8, 16, 19, 20, 21, and 24 displayed 1.6–3.5-fold increase in agonistic rates on 5-HT_1A receptor. Particularly, derivatives 7, 19, and 21 exhibited significant agonistic activities on MT₁ and 5-HT_1A receptors with EC₅₀ values of 0.51, 0.39, 0.50 mΜ and 0.28, 0.46, 0.23 mΜ, respectively. The preliminary structure–activity relationships of gramine derivatives were summarized for further investigation on MT₁ and 5-HT_1A receptors as new potential agonists.

Keywords:

• Gramine
• melatonin receptor
• 5-hydroxy-tryptamine receptor
• agonistic activity
• structure–activity relationships