CONFORMATIONAL-ANALYSIS OF 3 NK1 TRIPEPTIDE ANTAGONISTS - A PROTON NUCLEAR-MAGNETIC-RESONANCE STUDY

Two new peptides, tailored after Ac-Thr-D-Trp(CHO)-Phe-NMeBzl (TRI), n amely, Ac-Thr-D-Trp(CHO)-Phe-NMe alpha MeBzl (TRA) and Ac-Thr-D-Trp(CH O)-Oic-NMeBzl (TOI), in which Phe is replaced by (3aS,7aS)-octahydroin dole-2-carboxylic acid, proved more potent and selective NK1 antagonis ts. The conformational properties of all three compounds were investig ated in solution by NMR spectroscopy and those of TRI analysed in grea ter detail by means of systematic computer-assisted modelling. All con formers whose energy differs by less than 9 kcal/mol from the absolute minimum are different from the conformer proposed in a previous molec ular modelling study by the discoverers of TRI. Parallel calculations for TRA and TOI yield low-energy conformers similar to those of TRI bu t in a slightly different order. Comparison of the shapes of low-energ y conformers of all three peptides with those of four typical rigid NK 1 antagonists shows that putative bioactive conformations are indeed p resent in solution.