Design and Synthesis of Pyrazolomorphinan Derivatives as Novel Delta Opioid Receptor Agonists

We designed pyrazolomorphinan derivatives <b>3</b> as novel δ opioid receptor (DOR) selective agonists with an unprecedented chemotype according to the drug design concept for the DOR selective agonist KNT-127 which encompassed the message-address concept, the accessory site concept, and the conversion of an indole ring into a quinoline ring. The designed compounds <b>3</b> as well as their regioisomers <b>9</b> showed potent DOR agonistic activities with low or almost no activities for the μ (MOR) and κ opioid receptors (KOR). Among the tested compounds, SYK-1106 (<b>9j</b>) bearing a cyclohexyl substituent was the most potent and efficacious DOR agonist (DOR: EC₅₀ = 0.089 nM, <i>E</i>_max = 111%; agonistic activities for the MOR and KOR were not determined). SYK-1106 showed dose-dependent and DOR antagonist NTI reversible antidepressant-like effects at 0.3 mg/kg, s.c. in the mouse forced-swimming tests without an effect on locomotor activity and with no convulsive effects.