BENZOFURAN BIOISOSTERES OF HALLUCINOGENIC TRYPTAMINES

The benzofuran analogues of the hallucinogens 5-methoxy-NN-dimethyltryptamine and 5-methoxy-alpha-methyl-tryptamine were synthesized and evaluated for affinity at the serotonin 5-HT2 and 5-HT1A receptors in rat brain homogenate, labeled with [I-125]-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane ([I-125]DOI) and [H-3]-8-hydroxy-2-(N,N-di-n-propylamino)tetralin ([H-3]-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-HTA1A receptor, but decreased only about 20-30% from that of the indole isosteres. Thus, the 5-HT1A 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-HT1A receptor. It is suggested that benzofurans may be useful in the design of serotonin receptor ligands.