SYNTHESIS AND OPIATE ACTIVITY OF PSEUDO-TETRAPEPTIDES CONTAINING CHIRAL PIPERAZIN-2-ONE AND PIPERAZINE DERIVATIVES

Enantiomeric piperazin-2-one derivatives, N',N'-ethylene-bridged alany lphenylalanines (1a or 1b), were synthesized using (S)- or (R)-alanine and phenylalanine as starting materials, and were inserted into the s econd and third positions of enantiomeric pseudo-tetrapeptides (P1a-or P1b-OEt). The corresponding piperazine derivatives (1a-or 1b-sRed) ob tained by selective BH3 reduction of the amide carbonyl groups of 1a o h 1b were similarly inserted into the same positions of tetrapeptides (P1a- and P1b-sRed). Enantiomeric N,N'-ethylene-bridged tyrosyltyrosin e derivatives (2a or 2b obtained from (S)- or (R)-tyrosine were also i nserted into the first and second positions of two pairs of enantiomer ic tetrapeptides (P2a- and P25-OEt or P'2a- and P'2b-QEt). The opiate activities of the eight peptides thus obtained were studied by use of the mouse vas deferens and the guinea pig ileum assays in order to elu cidate the structure-activity relationships of these peptides, especia lly with respect to stereochemistry.