Synthesis of highly μ and δ opioid receptor selective peptides containing a photoaffinity group

Article abstract of DOI:10.1021/jm00123a023

A series of cyclic, conformationally constrained photolabile peptides related to the enkephalins and to somatostatin were designed and synthesized in an effort to develop highly selective and potent peptides for the δ and μ opioid receptors. The following new peptides were prepared and tested for their δ opioid receptor potency and selectivity in the guinea pig ileum assay, the mouse vas deferens assay, and the rat brain binding assay: H-Tyr-D-Pen-Gly-p-NH₂Phe-D-Pen-OH (1, [p-NH₂Phe⁴]DPDPE) and H-Tyr-D-Pen-Gly-p-N₃Phe-D-Pen-OH (2, [p-N₃Phe⁴]DPDPE). The following new peptides were prepared and tested for their μ opioid receptor potency and selectivity in the same assays: H-D-Phe-Cys-p-NH₂Phe-D-Trp-Lys-Thr-Pen-Thr-NH₂ (3, [p-NH₂Phe³]CTP) and D-Phe-Cys-p-N₃Phe-D-Trp-Lys-Thr-Pen-Thr-NH₂ (4, [p-N₃Phe³]CTP). The δ selective photoaffinity peptide 2 displayed both high affinity (IC₅₀ = 9.5 nM) and good selectivity (IC₅₀ μ/IC₅₀ δ = 1053) as an agonist at δ opioid receptors in bioassays, and 2 also displayed moderate affinity (33 nM) and excellent selectivity (IC₅₀ μ/IC₅₀ δ = 110) for rat brain δ opioid receptors. The μ selective photoaffinity peptide 4 displayed very weak affinity (8% contraction at 300 nM) at μ opioid receptors in bioassays, but good affinity (IC₅₀ = 48.6 nM) and excellent selectivity (IC₅₀ δ/IC₅₀ μ = 412) for the rat brain μ opioid receptors. These conformationally constrained cyclic photoaffinity peptides may be useful tools to investigate the pharmacology of δ and μ opioid receptors.