A Refined Model for the Somatostatin Pharmacophore: Conformational Analysis of Lanthionine−Sandostatin Analogs

We report the conformational analysis of a series of analogs of sandostatin (octreotide, D-Phe1-c[Cys2-Phe3-D-Trp4-Lys5-Thr6-Cys 7]-Thr8-ol) using 1H NMR spectroscopy and molecular modeling. Two active compounds in which the disulfide group is replaced by a monosulfide (lanthionine) bridge (D-Phe1-c[AlaL2-Phe3-D-Trp4-Lys5-Thr6-A laL7]-Thr8-ol and D-Phe1-c[AlaL2-Phe3-D-Trp4-Lys5-Thr6-Al aL7]-Thr8-NH2, where AlaL denotes each of the lanthionine amino acid ends linked by the monosulfide bridge) show different mSSTR2b/rSSTR5 receptor selectivities as compared to sandostatin. These new results have enabled us to reveal features of the somatostatin pharmacophore common to the model previously proposed in our laboratory on the basis of main chain and side chain chiral methylation studies. In addition, our studies provide new insight into the role of the disulfide bridge and of Thr8 in binding potency. We also show that the lanthionine group is a good mimetic of beta-VI turns and can be incorporated in sandostatin analogs maintaining the essential secondary structural features of sandostatin. These results facilitate the design of new sandostatin peptidomimetics.