Design and Synthesis of Conformationally Constrained Somatostatin Analogues with High Potency and Specificity for μ Opioid Receptors

A series of cyclic, conformationally constrained peptides related to somatostatin were designed and synthesized in an effort to develop highly selective and potent peptides for the μ opioid receptor. The following new peptides were prepared and tested for their μ opioid receptor potency and selectivity in 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); o-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); and D-PhGly-Pen-Phe-D-Trp-Lys-Thr-Cys-Thr-OH (10). The most selective peptide, 2 (CTOP), displayed both high affinity (IC₅₀= 3.5 nM) and exceptional selectivity (IC₅₀ δ/IC₅₀μ ^{= 4000)}for μ opioid receptors. Furthermore, 2 exhibited very low affinity for somatostatin receptors in the rat brain (IC₅₀ > 24000 nM), with an IC₅₀ somatostatin/IC₅₀μ receptor selectivity of 8750. These conformationally constrained cyclic peptides should provide new insight into the structural and conformational requirements for the μ opioid receptor and the physiological role of this receptor.