![]() Roles of affinity and lipophilicity in the onset kinetics of these and other prostanoid ligands were investigated. Jones, RL Woodward, DF Wang, JW Clark, RLīACKGROUND AND PURPOSE The highly lipophilic acyl-sulphonamides L-798106 and L-826266 showed surprisingly slow antagonism of the prostanoid EP3 receptor system in guinea-pig aorta. Roles of affinity and lipophilicity in the slow kinetics of prostanoid receptor antagonists on isolated smooth muscle preparations ![]() Reduction of the Lys-Dmt peptide bond in cyclodal resulted in an analogue, cDmt-] (8), with MOR agonist activity. Surprisingly, the mirror-image isomer (optical antipode) of cyclodal, c (2), also turned out to be a selective MOR antagonist with 1 nM binding affinity, and thus, these two compounds represent the first example of mirror image opioid receptor ligands with both optical antipodes having high binding affinity. Cyclodal showed high plasma stability and was able to cross the blood–brain barrier to reverse morphine-induced, centrally mediated analgesia when given intravenously. A docking study of cyclodal using the crystal structure of MOR in the inactive form showed a unique binding mode with the two basic residues of the ligand forming salt bridges with the Asp127 and Glu229 receptor residues. Head-to-tail cyclization of the μ opioid receptor (MOR) agonist DALDA (H-Dmt-d-Arg-Phe-Lys-NH2 (9 Dmt = 2′,6′-dimethyltyrosine) resulted in a highly active, selective MOR antagonist, c (1) (“cyclodalâ€), with subnanomolar binding affinity. Ge, Yang Laferrière, André Coderre, Terence J. Wood, JodiAnne Ma, Xiaoyu Guo, Jason Wilkes, Brian C. ![]() ![]() ![]() A Cyclic Tetrapeptide (“Cyclodalâ€) and Its Mirror-Image Isomer Are Both High-Affinity μ Opioid Receptor Antagonists ![]()
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