Discovery of δ Opioid Receptor Full Inverse Agonists and Their Effects on Restraint Stress-Induced Cognitive Impairment in Mice

The cyclopropylmethyl group in classical delta opioid receptor (DOR) antagonist NTI, BNTX, and NTB was replaced with various electron-withdrawing groups to develop DOR inverse agonists. N-Benzyl NTB derivative SYK-657 was a potent DOR full inverse agonist and its potency was over 10-fold potent than that of a reference compound ICI-174,864. Intraperitoneal administration of SYK-657 induced the short-term memory improving effect in mice without abnormal behaviors.