PYRIMIDO[5,4-B]INDOLE DERIVATIVES .1. A NEW CLASS OF POTENT AND SELECTIVE ALPHA-1 ADRENOCEPTOR LIGANDS

A number of 3-substituted pyrimido[5,4-b]indole-2,4-diones (7-23) were evaluated for their in vitro alpha-1 adrenoceptor affinity by radioligand receptor binding assays. Some compounds bearing a (phenylpiperazinyl)alkyl side chain were potent alpha-1 adrenoceptor ligands. The most active derivative in displacement of [H-3]prazosin from rat cortical membranes was 3-[2-[4-(2-methoxyphenyl)piperazin-1-yl]ethyl]pyrimido[5,4-b]indole-2,4-dione (10) (K(i) = 0.21 nM). Discrete modifications in the structure resulted in higher selectivity (> 10 000 times) for alpha-1 than alpha-2, beta-2, and 5HT1A receptors. Some compounds also had affinity for the 5HT1A receptor. The most selective alpha-1 ligand was 3-[2-[4-(2-chlorophenyl)piperazin-1-yl]ethyl]pyrimido[5,4-b]indole-2,4-dione (13).