Building a model of interaction at the NK-2 receptors: Polycondensed heterocycles containing the pyrimidoindole skeleton

The pyrazolopyrimidothiazole ring system (compound N, table II) has been previously reported by us as a new competitive antagonist (apparent pA₂ = 7.3 equiv to 55 nM) at NK2-receptors. As part of our investigation on polycondensed heterocycles containing the pyrimidine ring as antagonists of G-protein coupled receptors, pyrimidoindole derivatives were prepared and tested in order to probe the topography of the NK2-receptors and ascertain the pattern of frameworks that result in optimum affinity and specificity. The title indole derivatives 5, 11a-d, 12c, 13a,b and 14b were ‘de novo’ designed or selected from our chemical archives and prepared by up-to-date synthetic routes, thus exploring new synthetic methodologies. According to the established graphic computer model, none of the tested substances exhibited activity as a consequence of the violation of an excluded volume area due the unfavourable position of the aromatic substituents.