The 13-membered cyclic peptide, H-Tyr-D-Orn-Phe-Asp-NH2 (cyc-Orn-asp), is a potent mu-selective opioid peptide. Molecular modelling of this peptide has revealed considerable flexibility in the ring structure, making it difficult to identify a single conformation which may be biologically relevant. In order to restrict further the conformational mobility in this peptide and others, we have designed and synthesized a novel acid based on pyrrolidine (PDA). This amino acid, if used in place of Orn or Lys for side-chain-side-chain cyclization, is expected to reduce considerably the conformational flexibility in the macrocyclic ring of these peptides owing to the introduction of a bicyclic structure. Moreover, the additional asymmetric center in the pyrrolidine ring may introduce differential stereochemical constraints to the binding of diastereoisomeric peptides, derived from the corresponding diastereoisomeric PDA's. Thus, these peptides may act as probes for delineating the stereochemical topology of the receptor in the vicinity of the ring structure and may have useful biological properties and applications. Synthesis in the 2-pyrrolidinealanine series had been completed last year and parallel efforts in the 3-pyrrolidine series are almost finished. Optically active amino acids are being used increasingly as synthons for the preparation of a variety of chiral compounds. PDA's can be expected to be excellent synthons for compounds such as pyrrolizidines with the stereochemistry already defined at two centers. Furthermore, these amino acids may possess antimicrobial or other antimetabolic activities. An efficient method for the synthesis of all four optically active stereoisomers of 2-PDA has been developed. These amino acids will be used for the preparation of novel bicyclic opioid peptide analogues.
| Zhang, Ning; Appella, Daniel H (2010) Advantages of peptide nucleic acids as diagnostic platforms for detection of nucleic acids in resource-limited settings. J Infect Dis 201 Suppl 1:S42-5 |
