Our
previous results showed that naltrindole (NTI) derivatives
with certain types of electron-withdrawing groups as an N-substituent
showed δ opioid receptor (DOR) inverse agonistic activities.
We therefore synthesized N-acylated NTI derivatives 3a–e and observed that N-benzoyl
and N-cyclopropanecarbonyl derivatives SYK-736 (3b) and SYK-623 (3c) were DOR full inverse agonists
and the N-acryloyl derivative 3d was
a DOR partial inverse agonist. SKY-623 was over 110-fold more potent
than the reference compound ICI-174,864. Both naltriben (NTB) and
7-benzylidenenaltrexone (BNTX) derivatives with N-benzoyl and N-cyclopropanecarbonyl groups were
also DOR full inverse agonists. These N-acylated
inverse agonists are interesting compounds because they have no basic
nitrogen atom, which has been demonstrated to be an important pharmacophore.
NTI and BNTX-type DOR inverse agonists SYK-623 and SYK-723 (12c) showed dose-dependent antitussive effects in a mouse
cough model induced by citric acid exposure. The antitussive effects
by SYK-623 and SYK-723 were significantly attenuated by pretreatment
with DOR agonist SNC80.
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