Synthesis and Opiate Activity of Pseudo-Tetrapeptides Containing Chiral Piperazin-2-one and Piperazine Derivatives

• Published in: Chemical & pharmaceutical bulletin Vol. 45; no. 12; pp. 1940 - 1944
• Main Authors: YAMASHITA, Tetsushi, TSURU, Eiji, BANJYO, Eri, DOE, Matsumi, SHIBATA, Kozo, YASUDA, Masahide, GEMBA, Munekazu
• Format: Journal Article
• Language: English
• Published: Tokyo The Pharmaceutical Society of Japan 01-12-1997; Maruzen; Japan Science and Technology Agency
• Subjects: Alanine - chemistry; Animals; Biological and medical sciences; Biological Assay; Boron Compounds - chemistry; Bridged-Ring Compounds - chemical synthesis; Guinea Pigs; Male; Medical sciences; Mice; N, N'-ethylene-bridged dipeptide; Narcotics - chemical synthesis; Narcotics - pharmacology; Neuropharmacology; Neurotransmitters. Neurotransmission. Receptors; Oligopeptides - chemical synthesis; Oligopeptides - pharmacology; opiate activity; Peptidergic system (neuropeptide, opioid peptide, opiates...). Adenosinergic and purinergic systems; Pharmacology. Drug treatments; Phenylalanine - chemistry; piperazine derivative; Piperazines - chemical synthesis; Piperazines - chemistry; Piperazines - pharmacology; pseudo-tetrapeptide; selective BH3 reduction; Stereoisomerism; Structure-Activity Relationship; Peptides; Ligand; Opioid receptor; Lactam; Smooth muscle; Liquid phase; Chemical reduction; Guinea pig; Chemical synthesis; R configuration; Alanine; Borane; Phenylalanine; Rodentia; Steric hindrance; In vitro; Biological activity; Pseudopeptide; Vertebrata; Mammalia; Mouse; Animal; Peptide synthesis; Piperazine derivatives; Diastereomer
• DOI: 10.1248/cpb.45.1940
• EISSN: 1347-5223
• ISSN: 0009-2363

Enantiomeric piperazin-2-one derivatives, N, N'-ethylene-bridged alanylphenylalanines (1a or 1b), were synthesized using (S)- or (R)-alanine and phenylalanine as starting materials, and were inserted into the second and third positions of enantiomeric pseudo-tetrapeptides (P1a- or P1b-OEt). The corresponding piperazine derivatives (1a-or 1b-sRed) obtained by selective BH3 reduction of the amide carbonyl groups of 1a or 1b were similarly inserted into the same positions of tetrapeptides (P1a- and P1b-sRed). Enantiomeric N, N'-ethylene-bridged tyrosyltyrosine derivatives (2a or 2b) obtained from (S)- or (R)-tyrosine were also inserted into the first and second positions of two pairs of enantiomeric tetrapeptides (P2a- and P2b-OEt or P'2a- and P'2b-OEt). 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 elucidate the structure-activity relationships of these peptides, especially with respect to stereochemistry.