Pyrano[2,3,4-cd]indole as a Scaffold for Selective Nonbasic 5-HT₆R Ligands

In this letter, we report the synthesis of a pyrano[2,3,4-cd]indole chemical scaffold designed through a tandem bioisostere generation/virtual screening protocol in search of 5-HT₆R ligands. The discovered chemical scaffold resulted in the design of highly active basic and nonbasic 5-HT₆R ligands (5-HT₆R K_i = 1 nM for basic compound 6b and 5-HT₆R K_i = 4 nM for its neutral analog 7b). Additionally, molecular modeling suggested that the hydroxyl group of nonbasic ligands 7a-7d forms hydrogen bonds with aspartic acid D^3×32 or D^7.36×35.