A bicyclic and hsst2 selective somatostatin analogue: Design, synthesis, conformational analysis and binding

A backbone bridged and disulfide bridged bicyclic somatostatin analogue, co mpound 1 (PTR-3205), was designed and synthesized by solid-phase methodolog y. The binding of compound 1 to the five different somatostatin receptors, expressed in CHO or COS-7 cells, indicate a high degree of selectivity towa rds hsstr2. The three-dimensional structure of this compound has been deter mined in DMSO-d(6) and in water by H-1 NMR and by molecular dynamics simula tions. Similar backbone conformations were observed in both solvents. We ha ve established direct evidence that the backbone of this bicyclic somatosta tin analogue assumes a 'folded' conformation in solution, where the lactam ring extends roughly in the plane of the P-turn. The pharmacophoric region Phe-(D)-Trp-Lys-Thr of compound 1 is in accord with that of both the Veber compound L-363,301 (Merck) and sandostatin. We believe that the enhanced se lectivity towards the hsst2 receptor, in comparison with other analogues., is due to its large hydrophobic region, composed of the lactam ring and the Phe side chains at positions 1 and 8. (C) 2001 Elsevier Science Ltd. All r ights reserved.