Development of Novel Delta Opioid Receptor Inverse Agonists and Their Antitussive Effects

Abstract

We synthesized a delta opioid receptor (DOR) antagonist naltrindole (NTI) derivative SYK-165 with a 2,2,2-trifluoroethyl substitute on the 17-nitrogen and reported it showed DOR partial inverse agonist activity in [³⁵S] GTPγS binding assays (Bioorg. Med. Chem. Lett., 2015, 25, 2927-2930.). For the purpose of investigating the further structure-activity relationship, we designed and synthesized NTI derivatives with various electron-withdrawing groups at the 17-position to find a DOR full inverse agonist SYK-623, possessing a 17-cyclopropanecarbonyl group. SYK-623 was over 100-fold more potent than ICI-174,864, a standard DOR inverse agonist. We applied such modification to other DOR antagonists, 7-benzylidenenaltrexone (BNTX) and naltriben (NTB), which have respective chemotypes different from that of NTI. As a result, 17-cyclopropanecarbonyl derivatives SYK-723 (BNTX type) and SYK-724 (NTB type) were also potent DOR full inverse agonists. SYK-623, SYK-723, and SYK-724 are very interesting compounds because these compounds elicited potent DOR full inverse agonist activities in spite of the fact that they have no basic nitrogen, which is known to be indispensable functionality for the interaction with the opioid receptors.

We previously reported that opioidergic nerves system contributed to the control of cough reflex and that DOR antagonists induced antitussive effects (Pulm. Pharmacol. Ther., 2002, 15, 235-240.). We attempted to examine the effects of DOR inverse agonists on the cough reflex induced by citric acid in mice. Both SYK-623 and SYK-723 showed marked antitussive effects in a dose-dependent manner. We will report detailed results of in vitro and in vivo assays for DOR inverse agonists.