Synthesis and receptor activity of 2-substituted 8-methyl-5-(2-pyridinylethyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indoles

A series of new 2-substituted 8-methyl-5-(2-pyridinylethyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indoles have been synthesized. Their activity profiles were studied on a broad panel of therapeutic targets including GPC-receptors, ion channels, and neurotransmitter transporters. One of the studied compounds, 2-methyl-3-{2-[8-methyl-5-(2-pyridin-2-ylethyl)-2,3,4,5-tetrahydropyridino[4,3-b]indol-2-yl]ethyl}-6,7,8,9-tetrahydropyrido[1,2-a]pyrimidin-4-one, was found to be a highly active antagonist of adrenergic α1A, α1B, α1D, and α2A receptors and serotonin 5-HT2A, 5-HT2B, 5-HT2C, and 5-HT7 receptors. The results were considered in terms of structure—activity relationships. It was established that introduction of bulky substituents into the 2-position of the other synthesized 8-methyl-5-(2-pyridinylethyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indoles led to an activity decrease of the corresponding derivatives as compared with that of the 2,8-dimethyl analogs.