PYRIMIDO[5,4-B]BENZOFURAN AND PYRIMIDO[5,4-B]BENZOTHIOPHENE DERIVATIVES - LIGANDS FOR ALPHA-1-RECEPTORS 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 alpha1-adrenoceptor and 5HT1A-receptor affinities by radioligand receptor binding assays. All target compounds showed good to excellent affinities for the alpha1-adrenoceptor with K(i) values in the subnanomolar range. Some compounds were also good ligands for the 5HT1A-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 [H-3]-8-OH-DPAT from rat hippocampal membranes. There is evidence suggesting that the N1 methyl group of the tricyclic moiety of the title compounds is probably able to undergo a Van der Waals interaction at the 5HT1A-receptor binding site but not at the alpha1-adrenoceptor active site.