Lanthionine-somatostatin analogs: Synthesis, characterization, biological activity, and enzymatic stability studies

George Ösapay, Laszlo Prokai, Ho Seung Kim, Katalin F. Medzihradszky, David H. Coy, George Liapakis, Terry Reisine, Giuseppe Melacini, Qin Zhu, Susan H.H. Wang, Ralph Heiko Mattern, Murray Goodman

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Abstract

A series of cyclic somatostatin analogs containing a lanthionine bridge have been subjected to studies of structure-activity relationships. A direct synthesis of the thioether bridged analog (1) of sandostatin (SMS 201,995) and several lanthionine hexa-, hepta-, and octapeptides was carried out by using the method of cyclization on an oxime resin (PCOR) followed by condensation reactions in solution. The structures of the target peptides were analyzed by liquid secondary ion mass spectrometry (LSIMS) and subjected to high-energy collision-induced dissociation (CID) studies after opening of the peptide ring by proteolytic cleavage. The biological activities of these compounds have been evaluated by assaying their inhibitory potencies for the release of growth hormone (GH) from primary cultures of rat anterior pituitary cells, as well as by their binding affinities to cloned somatostatin receptors (SSTR1-5). The structural modification of sandostatin by introducing a lanthionine bridge resulted in a significantly increased receptor binding selectivity. The lanthionine octapeptide with C-terminal Thr-ol (1) showed similar high affinity for rat SSTR5 compared to somatostatin[1-14] and sandostatin. However, it exhibits about 50 times weaker binding affinity for mSSTR2b than sandostatin. Similarly, the lanthionine octapeptide with the C-terminal Thr-NH2 residue (2) has higher affinity for rSSTR5 than for mSSTR2B. Both peptides (compounds 1 and 2) have much lower potencies for inhibition of growth hormone secretion than sandostatin. This is consistent with their affinities to SSTR2, the receptor which is believed to be linked to the inhibition of growth hormone release by somatostatin and its analogs. The metabolic stability of lanthionine- sandostatin and sandostatin have been studied in rat brain homogenates. Although both compounds have a high stability toward enzymatic degradation, the lanthionine analog has a 2.4 times longer half-life than sandostatin. The main metabolites of both compounds have been isolated and identified by using an in vivo technique (cerebral microdialysis) and mass spectrometry.

Original languageEnglish
Pages (from-to)2241-2251
Number of pages11
JournalJournal of Medicinal Chemistry
Volume40
Issue number14
DOIs
StatePublished - 4 Jul 1997

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    Ösapay, G., Prokai, L., Kim, H. S., Medzihradszky, K. F., Coy, D. H., Liapakis, G., Reisine, T., Melacini, G., Zhu, Q., Wang, S. H. H., Mattern, R. H., & Goodman, M. (1997). Lanthionine-somatostatin analogs: Synthesis, characterization, biological activity, and enzymatic stability studies. Journal of Medicinal Chemistry, 40(14), 2241-2251. https://doi.org/10.1021/jm960850i