Design, Synthesis, and Structure-Affinity Relationship Studies in NK1 Receptor Ligands Based on Azole-Fused Quinolinecarboxamide Moieties

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. (c) 2008 Elsevier Ltd. All rights reserved.