Transforming Amino Acids into Serotonin 5-HT<sub>2A</sub> Receptor Ligands Using Photochemistry.
Abstract
A light-induced cyclization via a radical spin-center shift process that results in the direct functionalization of the indole ring at the C4-position is developed into a practical method for the synthesis of medicinally active, ring-constrained tryptamine analogs. Amino acids were coupled to tryptamine and irradiated with UV light to produce a library of lactams bridging the C3- and C4-positions of the indole nucleus. An extension to this method is introduced that employs α-acetoxy- and α-lactone-substituted tryptamides. Using optimized conditions and these easily accessed precursors, C3- to C4-bridged indoles can now be produced in good to excellent yields, free of the C2-regioisomers that are often seen using α-halo tryptamide substrates. Due to the structural similarities of the reduced lactams (azocinoindoles) with known psychoactive tryptamines, their functional activation at the serotonin 5-HT<sub>2A</sub> receptor was investigated both <i>in silico</i> and <i>in vitro</i>. These azocinoindoles show both full and partial agonist 5-HT<sub>2A</sub> Gq activation efficacies and suppress the head-twitch response in vivo, suggesting they belong to an emerging class of nonhallucinogenic 5-HT<sub>2A</sub> agonists. The azocinoindole core and the synthetic advances described here that enable its structural diversification provide a valuable platform for serotonin receptor drug discovery.
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