1.Dehydro-dermorphins. I. Influence of the stereo-orientation of aromatic groups in dermorphin-(1-5)-peptides to opioid activity.
Salvadori S;Marastoni M;Balboni G;Marzola G;Tomatis R Int J Pept Protein Res. 1986 Sep;28(3):254-61.
Dehydrophenylalanine having the Z-configuration (delta Phe) and D-Phe were incorporated in positions 3 and/or 5 into dermorphin-(1-5)-peptide amide (H-Tyr-D-Ala-Phe-Gly-Tyr-NH2) in order to study the effect of structure or configurational changes. On GPI preparation, whereas the activity of [L-Phe5]-pentapeptide was fourfold higher than parent peptide and comparable to that of dermorphin, the substitution of Phe3 by its D-enantiomer was barely tolerated. The pentapeptides containing delta Phe in positions 3 and/or 5 displayed even lower potency: particularly the unsaturation at position 3 alone or at position 3 and 5 was very detrimental to mu activity.
2.Characterization of the binding of [3H][Dmt1]H-Dmt-D-Arg-Phe-Lys-NH2, a highly potent opioid peptide.
Neilan CL;Janvey AJ;Bolan E;Berezowska I;Nguyen TM;Schiller PW;Pasternak GW J Pharmacol Exp Ther. 2003 Aug;306(2):430-6. Epub 2003 Mar 27.
The dermorphin-derived peptide [Dmt1]DALDA (H-Dmt-d-Arg-Phe-Lys-NH2; Dmt, 2',6'-dimethyltyrosine) labels mu-opioid receptors with high affinity and selectivity in receptor binding assays. In previous studies, [Dmt1]DALDA displayed a mechanism of action distinct from that of morphine, as evidenced by its insensitivity to antisense probes reducing morphine analgesia and incomplete cross tolerance to morphine. In an effort to further elucidate the unusual mechanism of action, [3H][Dmt1]DALDA has been synthesized and its binding profile studied. [3H][Dmt1]DALDA binding was high affinity (KD = 0.22 nM) and showed a regional distribution consistent with mu-receptors with highest levels in calf striatal membranes. [3H][Dmt1]DALDA binding was far less sensitive than [3H][d-Ala2,N-Me-Phe4,Gly5-ol]-enkephalin (DAMGO) to the effects of divalent and sodium cations and guanine nucleotides, although NaCl and guanosine 5'-(beta,gamma-imido)triphosphate together reduced specific [3H][Dmt1]DALDA binding levels by almost 75%. Competition studies confirmed the mu-selectivity of the binding, with Ki values that were not appreciably different from those seen against [3H]DAMGO. In guanosine 5'-O-(3-[35S]thio)-triphosphate ([35S]GTPgammaS) binding assays in brain and spinal cord membranes, [Dmt1]DALDA was more potent than DAMGO, but showed plateaus suggestive of a partial agonist.
3.siRNA capsulated brain-targeted nanoparticles specifically knock down OATP2B1 in mice: a mechanism for acute morphine tolerance suppression.
Yang ZZ;Li L;Wang L;Xu MC;An S;Jiang C;Gu JK;Wang ZJ;Yu LS;Zeng S Sci Rep. 2016 Sep 15;6:33338. doi: 10.1038/srep33338.
Regulating main brain-uptake transporter of morphine may restrict its tolerance generation, then modify its antinociception. In this study, more than 2 fold higher intracellular uptake concentrations for morphine and morphine-6-glucuronide (M6G) were observed in stable expression cells, HEK293-hOATP2B1 than HEK293-MOCK. Specifically, the Km value of morphine to OATP2B1 (57.58 ± 8.90 μM) is 1.4-time more than that of M6G (80.31 ± 21.75 μM); Cyclosporine A (CsA), an inhibitor of OATP2B1, can inhibit their intracellular accumulations with IC50 = 3.90 ± 0.50 μM for morphine and IC50 = 6.04 ± 0.86 μM for M6G, respectively. To further investigate the role of OATP2B1 in morphine brain transport and tolerance, the novel nanoparticles of DGL-PEG/dermorphin capsulated siRNA (OATP2B1) were applied to deliver siRNA into mouse brain. Along with OATP2B1 depressed, a main reduction was found for each of morphine or M6G in cerebrums or epencephalons of acute morphine tolerance mice. Furthermore, calcium/calmodulin-dependent protein kinase IIα (CaMKIIα) in mouse prefrontal cortex (mPFC) underwent dephosphorylation at Thr286. In conclusion, OATP2B1 downregulation in mouse brain can suppress tolerance via blocking morphine and M6G brain transport.
