STUDIES ON NEUROKININ ANTAGONISTS .3. DESIGN AND STRUCTURE-ACTIVITY-RELATIONSHIPS OF NEW BRANCHED TRIPEPTIDES N-ALPHA-(SUBSTITUTED L-ASPARTYL, L-ORNITHYL, OR YL)-N-METHYL-N-(PHENYLMETHYL)-L-PHENYLALANINAMIDES AS SUBSTANCE-P ANTAGONISTS

As an extension of our study on discovering a novel substance P (SP) a ntagonist, we designed new branched tripeptides containing L-aspartic acid (2 and 5), L-ornithine (3 and 6), and L-lysine (4 and 7) by recon structing the structure of the previously reported tripeptide SP antag onist [Ac-Thr-D-Trp(CHO)-Phe-NMeBzl FR113680]. The strategy for this d esign was based on the postulate that the dipeptide half D-Trp(CHO)-Ph e-NMeBzl in 1 is essential for receptor recognition. Molecular modelin g studies implied that these newly designed tripeptides could mimic th e spatial orientations of the essential dipeptide structure. As expect ed, all of these compounds potently inhibited H-3-SP (1 nM) binding to guinea pig lung membranes in the 10(-8) M range. The 1H-indol-3-ylcar bonyl derivatives (5-7) were slightly more potent than the correspondi ng 1H-indol-2-ylcarbonyl derivatives (2-4), as predicted by the molecu lar modeling studies. The structure-activity relationships studies on the selected 1H-indol-3-ylcarbonyl derivatives indicated that the thre onine moiety at the side chain can be modified into a variety of struc tures without any significant loss of the activity. Furthermore in the L-lysine series, even dipeptide compounds having nothing or a simple acyl group at the epsilon-amino group, such as syl]-N-methyl-N-(phenyl methyl)-L-phenylalaninamide (18b), exhibited potent activity. These di peptides belong to a new structural class of SP antagonist.