Pyrimido[5,4-b]benzofuran and pyrimido[5,4-b]benzothiophene derivatives Ligands for α1-and 5HT1A-receptors

A number of 3-phenylpiperazinylethyl pyrimido[5,4- b ]benzofuran-2,4-dione and pyrimido[5,4- b ]benzothiophene-2,4-dione derivatives 5–15 were designed as bioisosters of the previously reported pyrimido[5,4- b ]indole-2,4-diones and synthesized starting from the 3-amino-2-carboxybenzofuran and benzothiophene ethyl and methyl esters respectively. They were evaluated for their in vitro α 1 -adrenoceptor and 5HT 1A -receptor affinities by radioligand receptor binding assays. All target compounds showed good to excellent affinities for the α 1 -adrenoceptor with K i values in the subnanomolar range. Some compounds were also good ligands for the 5HT 1A -receptor with K i values in the nanomolar range. 3-[2-[4-(2-Methoxyphenyl)piperazin-1-yl]ethyl]-1-methyl pyrimido[5,4- b ]benzothiophen-2,4-dione 15 was the most active derivative in displacing [ 3 H]-8-OH-DPAT from rat hippocampal membranes. There is evidence suggesting that the N 1 methyl group of the tricyclic moiety of the title compounds is probably able to undergo a Van der Waals interaction at the 5HT 1A -receptor binding site but not at the α 1 -adrenoceptor active site.