A STRUCTURAL RATIONALE FOR THE DESIGN OF WATER-SOLUBLE PEPTIDE-DERIVED NEUROKININ-1 ANTAGONISTS

Molecular models of a pharmacophore for NK1 neurokinin antagonists and of ligand-receptor complexes for the human NK1 G protein-coupled rece ptor are presented. The models develop a structural rationale for the discovery of the recently described highly potent peptidomimetic NK1 a ntagonists S18523 and S19752 which were designed to be water soluble. Water solubility was conferred on these compounds by introduction of a n anionic butyl-tetrazole substituent on the scaffold of dipeptide-der ived NK1 antagonist analogues. The models provide convincing evidence that the anionic butyl-tetrazole moieties of S18523 and S19752 protrud e outside the membrane-spanning domain of the receptor and do not inte rfere significantly with the core of the antagonist binding site. It i s emphazised that this result could only be obtained through the combi nation of the two modelling approaches. The result suggest a general w ay to modify the transport properties of the peptidomimetic antagonist s without altering the receptor-binding interaction, and it outlines t he potential of including the combination of pharmacophore models and crude models of receptor-ligand complexes early in the drug design pro cess.