A flexible approach to the design of new potent substance P receptor ligands

The development of small-molecule antagonists of the substance-P-preferring tachykinin NK1 receptor offers an excellent opportunity to exploit these m olecules as novel therapeutic agents in diverse pathologies such as depress ion, emesis or asthma. GR71251 has previously been identified as a potent a nd selective substance-P-receptor antagonist. We have therefore undertaken the synthesis of new pseudopeptidic analogues based on the C-terminal seque nce of GR71251. The evaluation of binding affinities toward NK1 and NK2 rec eptors has enabled us to propose new selective NK1 ligands with high affini ty. Structure-activity relationships showed that the Trp-OBzl(CF3)(2) moiet y is essential for NK1 affinity and that the introduction of building units such as spirolactam, lactam or proline, leading to a constrained peptide, increased selectivity for NK1 receptors. These compounds constitute a usefu l starting point for new substance P antagonists and represent an attractiv e lead series for further studies on the design of specific NK1 antagonists .