Design and synthesis of conformationally constrained somatostatin analogues with high potency and specificity for μ opioid receptors

摘要: A series of cyclic, conformationally constrained peptides related to somatostatin were designed and synthesized in an effort develop highly selective potent for the mu opioid receptor. The following new prepared tested their receptor potency selectively rat brain binding assays: D-Phe-Cys-Tyr-D-Trp-Orn-Thr-Pen-Thr-NH2 (2, CTOP); D-Phe-Cys-Tyr-D-Trp-Arg-Thr-Pen-Thr-NH2 (3, CTAP); D-Phe-Cys-Tyr-D-Trp-Nle-Thr-Pen-Thr-NH2 (4); D-Phe-Cys-Tyr-D-Trp-Lys-Val-Pen-Thr-NH2 (5); D-Phe-Cys-Tyr-D-Trp-Lys-Gly-Pen-Thr-NH2 (6); D-Phe-Cys-Tyr-Trp-Lys-Thr-Pen-Thr-NH2 (7); D-Tyr-Cys-Tyr-D-Trp-Lys-Thr-Cys-Thr-OH (8); D-PhGly-Cys-Tyr-D-Trp-Lys-Thr-Pen-Thr-NH2 (9); D-PhGly-Pen-Phe-D-Trp-Lys-Thr-Cys-Thr-OH (10). most peptide, 2 (CTOP), displayed both high affinity (IC50 = 3.5 nM) exceptional selectivity delta/IC50 4,000) receptors. Furthermore, exhibited very low receptors greater than 24,000 nM), with IC50 somatostatin/IC50 8,750. These cyclic should provide insight into structural conformational requirements physiological role this