1. Development of disulfide-functionalized peptides covalently binding G protein-coupled receptors
Jürgen Einsiedel, Maximilian F Schmidt, Harald Hübner, Peter Gmeiner Bioorg Med Chem . 2022 May 1;61:116720. doi: 10.1016/j.bmc.2022.116720.
A broadly applicable synthesis of peptides incorporating mixed disulfides between cysteine and homocysteine and cysteamine was developed. The method was established using pharmacologically relevant G protein-coupled receptor (GPCR) ligands including the μ-receptor agonist Dmt-DALDA and extended to the orexin derivative Oxa(17-33) and NT(8-13), the C-terminal hexapeptide of neurotensin. The newly developed NT(8-13) analog 6b incorporating an S-functionalized homocysteine revealed covalent binding of the neurotensin receptor 1 (NTSR1) in a radioligand depletion study.
2. Choline-Sigma-1R as an Additional Mechanism for Potentiation of Orexin by Cocaine
Eugen Brailoiu, G Cristina Brailoiu, Pingwei Zhao, Jeffrey L Barr Int J Mol Sci . 2021 May 13;22(10):5160. doi: 10.3390/ijms22105160.
Orexin A, an endogenous peptide involved in several functions including reward, acts via activation of orexin receptors OX1and OX2, Gq-coupled GPCRs. We examined the effect of a selective OX1agonist, OXA (17-33) on cytosolic calcium concentration, [Ca2+]i, in neurons of nucleus accumbens, an important area in the reward circuit. OXA (17-33) increased [Ca2+]iin a dose-dependent manner; the effect was prevented by SB-334867, a selective OX1receptors antagonist. In Ca2+-free saline, the OXA (17-33)-induced increase in [Ca2+]iwas not affected by pretreatment with bafilomycin A1, an endo-lysosomal calcium disrupter, but was blocked by 2-APB and xestospongin C, antagonists of inositol-1,4,5-trisphosphate (IP3) receptors. Pretreatment with VU0155056, PLD inhibitor, or BD-1047 and NE-100, Sigma-1R antagonists, reduced the [Ca2+]iresponse elicited by OXA (17-33). Cocaine potentiated the increase in [Ca2+]iby OXA (17-33); the potentiation was abolished by Sigma-1R antagonists. Our results support an additional signaling mechanism for orexin A-OX1via choline-Sigma-1R and a critical role for Sigma-1R in the cocaine-orexin A interaction in nucleus accumbens neurons.
3. (2E,25E)-11,14,17,33,36,39,42-Hepta-oxa-penta-cyclo-[41.4.0.0.0.0]hepta-tetra-conta-1(43),2,5(10),6,8,18,20,22,25,27,29,31,44,46-tetra-decaene-4,24-dione
Truong Hong Hieu, Victor N Khrustalev, Le Tuan Anh, Anatoly T Soldatenkov, Svetlana A Soldatova Acta Crystallogr Sect E Struct Rep Online . 2011 May 1;67(Pt 5):o1128-9. doi: 10.1107/S1600536811013201.
The title compound, C(40)H(40)O(9), is a product of the double crotonic condensation of bis-(2-acetyl-phen-oxy)-3-oxapentane with bis-(2-formyl-phen-oxy)-3,6-dioxaoctane. The title macromolecule includes the 31-crown-7-ether skeletal unit and adopts a saddle-like conformation. The two ethyl-ene fragments have E configurations. The volume of the inter-nal cavity of the macrocycle is approximately 125 Å(3). In the crystal, the mol-ecules are arranged at van der Waals distances.
