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

Abstract

The cyclopropylmethyl group in classical δ 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.

Discovery of Novel Delta Opioid Receptor (DOR) Inverse Agonist and Irreversible (Non-Competitive) Antagonists

“…As noted in the Introduction, a limited set of DOR irreversible antagonists and inverse agonists has been discovered and reported [5,6,[8][9][10][11][12][13][14]21,22]. The ligands we report here were developed from a novel naltrexone scaffold and thus represent a significant contribution to the limited set of pharmacological tools available to probe the DOR.…”

Effects of N-Substituents on the Functional Activities of Naltrindole Derivatives for the δ Opioid Receptor: Synthesis and Evaluation of Sulfonamide Derivatives

“…Compound 7 [ 24 , 25 ], which is the key intermediate for the synthesis of the target sulfonamide-type NTI derivatives, was synthesized from naltrexone hydrochloride ( 1 ) ( Scheme 1 ). Fischer indolization of 1 with phenylhydrazine hydrochloride gave NTI ( 2 ) [ 27 , 28 ] in 99% yield, which was treated with acetic anhydride to afford diacetate 3 in 95% yield.…”

“…Finally, the key intermediate 7 was prepared by introduction of TBS group at the phenolic hydroxy group of 5 . Although we previously reported the synthesis of 7 from 1 [ 24 ], the synthetic method shown in Scheme 1 was four steps shorter and provided the key intermediate 7 in higher total yield than the previous method (see the Supporting Information for details). Portoghese et al and Rice et al independently reported the synthesis of the 5 hydrochloride from noroxymorphone in one step (see the Supporting Information for details) [ 45 , 46 ].…”

“…In the opioid field, since Costa and Herz firstly reported that peptidic ICI-174,864 showed δ opioid receptor (DOR) inverse agonist activity [ 21 ], several peptidic and non-peptidic DOR inverse agonists have been developed [ 4 ]. Possible pharmacological effects resulting from DOR inverse agonism include anorexia [ 22 , 23 ], short-term memory improvement [ 24 ], and antitussive effects [ 25 ]. We also recently reported several DOR inverse agonists with the skeleton of naltrindole (NTI) [ 24 , 25 , 26 ], which was developed as a selective DOR antagonist by Portoghese et al [ 27 , 28 ].…”

“…Interestingly, a series of compounds we reported induced activities from full inverse agonists to full agonists depending on their substituents on the 17-nitrogen atom ( Figure 1 ) [ 24 , 25 , 26 , 29 ]. Amide-type compound SKY-623 bearing 17-cyclopropanecarbonyl group was a DOR full inverse agonist with high potency [ 25 ].…”