Benzofuran Bioisosteres of Hallucinogenic Tryptamines

The benzofuran analogues of the hallucinogens 5-methoxy-N,N-dimethyltryptamine and 5-methoxy-α-methyltryptamine were synthesized and evaluated for affinity at the serotonin 5-HT₂ and 5-HT_1A receptors in rat brain homogenate, labeled with [¹²⁵I]-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane ([¹²⁵I]DOI) and [³H]-8-hydroxy-2-(N,N-di-n-propylamino)tetralin ([³H]-8-OH-DPAT), respectively. At the 5-HT₂ receptor, the benzofurans had slightly decreased affinities, approximately one-third and one-sixth those of the indoles, for the primary amines and the tertiary amines, respectively. The benzofurans also had lower affinity at the 5-HT_1A receptor, but decreased only about 20-30% from that of the indole isosteres. Thus, the 5-HT_1A receptor is less discriminating with respect to preference for an indole versus a benzofuran, although all of the compounds did have higher affinities for the 5-HT₂ receptor than for the 5-HT₂ receptor. It is suggested that benzofurans may be useful in the design of serotonin receptor ligands.