Design, synthesis, and structure–affinity relationship studies in NK1 receptor ligands based on azole-fused quinolinecarboxamide moieties Original Research Article

The substituent in position 2 of the quinoline nucleus of NK1 receptor ligands 5 has been constrained into different five-membered heterocyclic moieties in order to obtain information on the binding site pocket interacting with this apparently critical portion of ligands 5. This structure–affinity relationship study led to the discovery of novel tricyclic NK1 receptor ligands 6 showing affinity in the nanomolar range to the sub-micromolar one. The systematic structure variation suggests that electronic features of the tricyclic moiety play a role in modulating the interaction of these amide derivatives with their receptor.