NMR-Solution Structures and Affinities for the Human Somatostatin G-Protein-Coupled Receptors hsst(1-5) of CF3 Derivatives of Sandostatin (R) (Octreotide)

The previously reported (Helv. Chim. Acta 2008, 91, 2035) derivatives of octreotide (1) with a (CF3)-Trp substitution, i.e., 3, and with open-chain structures, i.e., 2, 4, and 5, have been tested for their affinities to hsst(1-5) receptors and subjected to a detailed NMR analysis. Their affinities vary from 15 nM to 5 mu m, as compared to 0.6 nM to 0.8 mu m for octreotide itself (Table 1). This decreased bioactivity may have had to be expected for the open-chain compounds 4 and 5; possible reasons for this decrease in the case of CF3 derivative of octreotide, 3, are discussed. NMR Analysis (Tables 2 and 3) provides evidence for increased dynamics of all new derivatives 2-5. The dynamics of the octreotide molecule 1 was analyzed by (natural-abundance) longitudinal C-13-T-1-relaxation time measurements (Table4), from which the conclusion is drawn that the backbone of the macrocycle is rather rigid on the time scale of this method.