We have recently reported that -alkyl and -acyl naltrindole (NTI) derivatives showed activities for the δ opioid receptor (DOR) ranging widely from full inverse agonists to full agonists. We newly designed sulfonamide-type NTI derivatives in order to investigate the effects of the -substituent on the functional activities because the side chain and S=O part in the sulfonamide moiety located in spatially different positions compared with those in the alkylamine and amide moieties. Among the tested compounds, cyclopropylsulfonamide (SYK-839) was the most potent full inverse agonist for the DOR, whereas phenethylsulfonamide (SYK-901) showed full DOR agonist activity with moderate potency.
View Article and Find Full Text PDFWe have recently reported that the elaboration of the N-substituent in the δ opioid receptor (DOR) antagonist naltrindole (NTI) enabled the regulation of the DOR activities from full inverse agonists to weak partial agonists. The investigations of amide-type NTI derivatives revealed that N-phenylacetyl and N-dihydrocinnamoyl derivatives 3a and 3b were DOR full agonists. The same transformations were applied to a DOR agonist KNT-127 to provide the more potent DOR agonists 6a and 6b.
View Article and Find Full Text PDFOur 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 - and observed that -benzoyl and -cyclopropanecarbonyl derivatives SYK-736 () and SYK-623 () were DOR full inverse agonists and the -acryloyl derivative was a DOR partial inverse agonist. SKY-623 was over 110-fold more potent than the reference compound ICI-174,864.
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