A bicyclic and hsst2 selective somatostatin analogue: Design, synthesis, conformational analysis and binding

Eliezer Falb, Yoseph Salitra, Tamar Yechezkel, Moshe Bracha, Pninit Litman, Roberto Olender, Rakefet Rosenfeld, Hanoch Senderowitz, Shaokai Jiang, Murray Goodman

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27 Scopus citations


A backbone bridged and disulfide bridged bicyclic somatostatin analogue, compound 1 (PTR-3205), was designed and synthesized by solid-phase methodology. The binding of compound 1 to the five different somatostatin receptors, expressed in CHO or COS-7 cells, indicate a high degree of selectivity towards hsstr2. The three-dimensional structure of this compound has been determined in DMSO-d(6) and in water by 1H NMR and by molecular dynamics simulations. Similar backbone conformations were observed in both solvents. We have established direct evidence that the backbone of this bicyclic somatostatin analogue assumes a 'folded' conformation in solution, where the lactam ring extends roughly in the plane of the beta-turn. The pharmacophoric region Phe-(D)-Trp-Lys-Thr of compound 1 is in accord with that of both the Veber compound L-363,301 (Merck) and sandostatin. We believe that the enhanced selectivity towards the hsst2 receptor, in comparison with other analogues, is due to its large hydrophobic region, composed of the lactam ring and the Phe side chains at positions 1 and 8.

Original languageEnglish
Pages (from-to)3255-3264
Number of pages10
JournalBioorganic and Medicinal Chemistry
Issue number12
StatePublished - Dec 2001
Externally publishedYes

Bibliographical note

Funding Information:
We wish to thank the National Institutes of Health (DK15410) for their financial support. The purification of compounds 1 and 2 was performed by Manuela Lazarov and Dvira Shohat from Peptor's analytical group. We gratefully acknowledge their invaluable help. We acknowledge Juliann Kwak for her critical reading of the manuscript and Nicole Smith for her help in preparing the figures, as well as Sandra Blaj Moore for the Introduction, revision and preparation of the manuscript for submission.


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