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Linear, Peptidase‐Resistant β 2 / β 3 ‐Di‐ and α / β 3 ‐Tetrapeptide Derivatives with Nanomolar Affinities to a Human Somatostatin Receptor, Preliminary Communication
Author(s) -
Seebach Dieter,
Rueping Magnus,
Arvidsson Per I.,
Kimmerlin Thierry,
Micuch Peter,
Noti Christian,
Langenegger Daniel,
Hoyer Daniel
Publication year - 2001
Publication title -
helvetica chimica acta
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.74
H-Index - 82
eISSN - 1522-2675
pISSN - 0018-019X
DOI - 10.1002/1522-2675(20011114)84:11<3503::aid-hlca3503>3.0.co;2-a
Subject(s) - tetrapeptide , chemistry , dipeptide , affinities , stereochemistry , binding affinities , peptide , amino acid , somatostatin receptor , amide , somatostatin , receptor , biochemistry , neuroscience , biology
N ‐Acyl‐ β 2 / β 3 ‐dipeptide‐amide somatostatin analogs, 5 – 8 , with β 2 ‐HTrp‐ β 3 ‐HLys ('natural' sequence) and β 2 ‐HLys‐ β 3 ‐HTrp ( retro ‐sequence) have been synthesized (in solution). Depending on their relative configurations and on the nature of the terminal N ‐acyl and terminal C ‐amino group, the linear β ‐dipeptide derivatives have affinities for the human receptor hsst 4, ranging from 250 to >10000 nanomolar ( Fig. 3 ). Also, N ‐Ac‐tetrapeptide amides 9 and 10 , which contain one α ‐ and three β ‐amino acid residues ( N ‐ β ‐ α ‐ β ‐ β ‐ C ), have been prepared (solid‐phase synthesis), with the natural (Phe, Trp, Lys, Thr) and the retro ‐sequence (Thr, Lys, Trp, Phe) of side chains and with two different configurations, each, of the two central amino acid residues. The novel ‘mixed', linear α / β ‐peptides have affinities for the hsst 4 receptor ranging from 23 to >10000 nanomolar ( Fig. 4 ), and, like ‘pure' β ‐peptides, they are completely stable to a series of proteolytic enzymes. Thus, the peptidic turn of the cyclic tetradecapeptide somatostatin ( Fig. 1 ) can be mimicked by simple linear di‐ and tetrapeptides. The tendency of β ‐dipeptides for forming hydrogen‐bonded rings is confirmed by calculations at the B3LYP/6‐31G(d,p) level ( Fig. 2 ). The reported results open new avenues for the design of low‐molecular‐weight peptidic drugs.