M. Gobbo, L. Biondi, F. Filira
2001
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Abstract
N-Benzylglycine (Nphe) is an achiral structural isomer of phenylalanine that may be useful as an amino acid replacement in SAR studies. The first incorporation of Nphe into a biologically active peptide was reported by using bradykinin (BK) [1]. In continuation of our investigations on the structure-activity relationship of BK and BK analogues [2] we focused our attention on Thr6-BK (H-Arg-Pro-Pro-Gly-Phe-Thr-Pro-Phe-Arg-OH), a native kinin discovered in the venom of a solitary wasp and present also in ant venom and in frog skin. Thr6-BK proved to be about 10 times more potent than BK in the insect central nervous system [3] as well as in stimulating smooth muscle contraction [4]. The structural analysis of Thr6-BK and its analogues is made particularly interesting by the fact that despite the high sequence homology with native BK (only one conservative substitution: Ser6/Thr6) there is a marked and significant difference in the biological profile of the two peptides. The conformation of the native Thr6-BK has been already investigated in DMSO by NMR spectroscopy and computer simulations [5]. We report in this communication the synthesis and some preliminary pharmacological experiments and structural investigations of new linear and cyclic Thr6-BK analogues in which either one or both the Phe residues in the peptide sequence have been substituted by N-benzylglycine.