LANTHIONINE-SOMATOSTATIN ANALOGS - SYNTHESIS, CHARACTERIZATION, BIOLOGICAL-ACTIVITY, AND ENZYMATIC STABILITY STUDIES

A series of cyclic somatostatin analogs containing a lanthionine bridg e 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 o f the target peptides were analyzed by liquid secondary ion mass spect rometry (LSIMS) and subjected to high-energy collision-induced dissoci ation (CID) studies after opening of the peptide ring by proteolytic c leavage. The biological activities of these compounds have been evalua ted by assaying their inhibitory potencies for the release of growth h ormone (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 bind ing 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 bind ing affinity for mSSTR2b than sandostatin. Similarly, the lanthionine octapeptide with the C-terminal Thr-NH2 residue (2) has higher affinit y for rSSTR5 than for mSSTR2B. Both peptides (compounds 1 and 2) have much lower potencies for inhibition of growth hormone secretion than s andostatin. This is consistent with their affinities to SSTR2, the rec eptor which is believed to be linked to the inhibition of growth hormo ne release by somatostatin and its analogs. The metabolic stability of lanthionine-sandostatin and sandostatin have been studied in rat brai n homogenates. Although both compounds have a high stability toward en zymatic degradation, the lanthionine analog has a 2.4 times longer hal f-life than sandostatin. The main metabolites of both compounds have b een isolated and identified by using an in vivo technique (cerebral mi crodialysis) and mass spectrometry.