A REFINED MODEL FOR THE SOMATOSTATIN PHARMACOPHORE - CONFORMATIONAL-ANALYSIS OF LANTHIONINE-SANDOSTATIN ANALOGS

We report the conformational analysis of a series of analogs of sandos tatin (octreotide, )-Phe(3)-D-Trp(4)-Lys(5)-Thr(6)-Cys(7)]-Thr(8)-ol) using H-1 NMR spectroscopy and molecular modeling. Two active compound s in which the disulfide group is replaced by a monosulfide (lanthioni ne) bridge Phe(3)-D-Trp(4)-Lys(5)-Thr(6)-Ala(L)(7)]-Thr(8)-ol and e(3) -D-Trp(4)-Lys(5)-Thr(6)-Ala(L)(7)]-Thr(8)-NH2, where Ala(L) denotes ea ch 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 t he somatostatin pharmacophore common to the model previously proposed in our laboratory on the basis of main chain and side chain chiral met hylation studies. In addition, our studies provide new insight into th e role of the disulfide bridge and of Thr(8) in binding potency. We al so show that the lanthionine group is a good mimetic of beta-VI turns and can be incorporated in sandostatin analogs maintaining the essenti al secondary structural features of sandostatin. These results facilit ate the design of new sandostatin peptidomimetics.