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

We
designed pyrazolomorphinan derivatives 3 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 3 as well as
their regioisomers 9 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 (9j) bearing a cyclohexyl substituent was the most potent and
efficacious DOR agonist (DOR: EC50 = 0.089 nM, Emax = 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.