C-terminal modified Enkephalin-like tetrapeptides with enhanced affinities at the kappa opioid receptor and monoamine transporters. (1st December 2021)

• Record Type: Journal Article
• Authors: Mehr-un-Nisa, ; Munawar, Munawar A.; Rankin, David; Hruby, Victor J.; Porreca, Frank; Lee, Yeon Sun
• Is Part Of: Bioorganic & medicinal chemistry. Volume 51(2021)
• Publication Date: 2021-12-01
• Subjects: Opioids -- Monoamine neurotransmitter-uptake inhibitors -- Multifunctional ligands -- Synergistic effect -- Analgesics; ACE atomic contact energy -- AcOH acetic acid -- Boc tert-butyloxycarbonyl -- BOP (benzotriazole-1-yloxy)-tris(dimethylamino)-phosphonium hexafluorophosphate -- Bn Benzyl -- BuOH Butanol -- CHO Chinese hamster ovary -- DALEA [d-Ala2, Leu5] enkephalin amide -- DAT dopamine transporter -- DIEA diisopropylethylamine -- DMF N, N-dimethylformamide -- hDOR human delta opioid receptor -- DPDPE c[d-Pen2, d-Pen5]enkephalin -- DAMGO [d-Ala2, NMePhe4, Gly5-ol]enkephalin -- Dmt 2, 6-dimethyltyrosine -- EtOAc ethyl acetate -- HBTU O-(benzotriazol-1-yl)-N, N, N′, N′-tetramethyluroniumhexafluorophosphate -- HEK human embryonic kidney -- HRMS high resolution mass spectrometry -- 5-HT 5-hydroxytryptamine -- hKOR human kappa opioid receptor -- LRMS low resolution mass spectrometry -- MVD mouse vas deferens -- NET norepinephrine transporter -- NMM N-methylmorpholine -- PDB protein data bank -- pTsOH p-toluenesulfonic acid -- RP-HPLC reversedphase-high performance liquid chromatography -- rMOR rat mu opioid receptor -- SAR structure–activity relationship -- SERT serotonin transporter -- SNRIs serotonin/norepinephrine re-uptake inhibitors -- SSRIs selective serotonin reuptake inhibitors -- TCA tricyclic antidepressants -- TEA triethylamine -- TFA trifluoroacetic acid -- Tic 1, 2, 3, 4-tetrahydroisoquinoline-3-carboxylic acid -- TLC thin layer chromatography -- TMS tetramethylsilane; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; Chemistry, Clinical -- Periodicals; Chemistry, Organic -- Periodicals; Chimie bio-organique -- Périodiques; Chimie pharmaceutique -- Périodiques; 615.19
• DOI: 10.1016/j.bmc.2021.116509
• Languages: English
• ISSNs: 0968-0896

Abstract

Graphical abstract: Abstract: A new series of enkephalin-like tetrapeptide analogs modified at the C -terminus by an N -(3, 4-dichlorophenyl)- N -(piperidin-4-yl)propionamide (DPP) moiety were designed, synthesized, and tested for their binding affinities at opioid receptors and monoamine transporters to evaluate their potential multifunctional activity for the treatment of chronic pain. Most ligands exhibited high binding affinities in the nanomolar range at the opioid receptors with a slight delta-opioid receptor (DOR) selectivity over mu-opioid receptor (MOR) and kappa-opioid receptor (KOR) and low binding affinities in the micromolar range at the monoamine transporters, SERT and NET. Ligands of which the positions 1 and 4 were substituted by Dmt and Phe(4-X) residues, respectively, showed the excellent binding affinities at three opioid receptors. Among them, Dmt- d -Tic-Gly-Phe(4-F)-DPP was the most promising considering its excellent opioid affinities, particularly unexpected high binding affinity ( K i = 0.13 nM) at the KOR, and moderate interactions with serotonin/norepinephrine reuptake inhibitors (SNRIs). Docking studies revealed that the ligand was a good fit for the KOR binding pocket (binding score = 8, 750).