作者: Seebohm, Guiscard ; Schreiber, Julian A. ; Schepmann, Dirk ; Daniliuc, Constantin ; Wünsch, Bernhard ; Fröhlich, Roland ; Goerges, Gunnar ; Frehland, Bastian ; Markus, Alexander

AbstractNegative allosteric modulators of N‐methyl‐ d‐aspartate receptors containing the GluN2B subunit represent promising drug candidates for the treatment of various neurological disorders including stroke, epilepsy, and Parkinson's disease. To increase the bioavailability and GluN2B affinity, the phenol of the potent benzazepine‐based inhibitor, WMS‐1410 (3), was replaced bioisosterically by a benzoxazolone moiety and the phenylbutyl side chain was conformationally restricted in a phenylcyclohexyl substituent. A four‐step, one‐pot procedure transformed the oxazolo‐benzazepine 7 into the phenylcyclohexyl derivative 11. The same protocol was applied to the methylated analog 12, which unexpectedly led to ring‐contracted oxazolo‐isoquinolines 18. This rearrangement was explained by the additional methyl moiety in the 8‐position inhibiting the formation of the planar intermediate iminium ion with phenylcyclohexanone. The allyl protective group of 11 and 18 was removed with RhCl3 and HCl to obtain the tricyclic compounds 5 and 19 without substituent at the oxazolone ring. The structures of the rearranged products 18 and 19 were elucidated by X‐ray crystal structure analysis. The oxazolo‐isoquinoline trans‐18 with allyl moiety (Ki = 89 nM) and the oxazolo‐benzazepine 5 without substituent at the oxazolone ring (Ki = 114 nM) showed GluN2B affinity in the same range as the lead compound 3. In two‐electrode voltage clamp measurements, 5 displayed only weak inhibitory activity.

2022-06-01·Archiv der Pharmazie4区 · 医学

Synthesis of oxazolo‐annulated 3‐benzazepines designed by merging two negative allosteric NMDA receptor modulators

4区 · 医学

Article

作者: Wünsch, Bernhard ; Schepmann, Dirk ; Markus, Alexander

AbstractTo improve the metabolic stability and receptor selectivity of ifenprodil (1), the benzoxazolone moiety of besonprodil (2) and the 3‐benzazepone moiety of WMS‐1410 (3) were merged to obtain oxazolobenzazepines of type 4. The 5‐(hydroxyethyl)benzoxazolone 7 representing the first key intermediate was prepared in four steps starting with the 4‐(2‐hydroxyethyl)phenol (8). Mitsunobu reaction of primary alcohol 7 with N‐sulfonylated glycine esters established the necessary side chain. The intramolecular Friedel–Crafts acylation of acid 12a containing the N‐tosyl protective group led upon decarbonylation exclusively to the tricyclic tetrahydroisoquinoline 14. Protection of the amino moiety by the stronger electron‐withdrawing triflyl group resulted in the desired 3‐benzazepine 15 without the formation of analogous isoquinoline. The triflyl protective group was cleaved off by K2CO3‐induced elimination of trifluoromethanesulfinate. In a one‐pot three‐step procedure, various oxazolobenzazepinediones 15 were obtained, which were reduced to afford the desired secondary alcohols 18.

2021-12-01·Journal of Pharmacology and Experimental Therapeutics3区 · 医学

Selective Inhibition of N-Methyl-d-aspartate Receptors with GluN2B Subunit Protects β Cells against Stress-Induced Apoptotic Cell Death

3区 · 医学

Article

作者: Hurtado, Héctor Noguera ; Wünsch, Bernhard ; Gresch, Anne ; De Luca, Vivien ; Wörmeyer, Laura ; Seebohm, Guiscard ; Wiggers, Rebekka ; Düfer, Martina

Participation of N-methyl-d-aspartate (NMDA) receptors (NMDARs) in the failure of pancreatic β cells during development of type 2 diabetes mellitus is discussed. Our study investigates whether β cell mass and function can be preserved by selectively addressing the GluN2B subunit of the NMDAR. NMDAR activation by NMDA and its coagonist glycine moderately influenced electrical activity and Ca²⁺ handling in islet cells at a threshold glucose concentration (4-5 mM) without affecting glucose-mediated insulin secretion. Exposure of islet cells to NMDA/glycine or a glucolipotoxic milieu increased apoptosis by 5% and 8%, respectively. The GluN2B-specific NMDAR antagonist WMS-1410 (0.1 and 1 µM) partly protected against this. In addition, WMS-1410 completely prevented the decrease in insulin secretion of about 32% provoked by a 24-hour-treatment with NMDA/glycine. WMS-1410 eliminated NMDA-induced changes in the oxidation status of the islet cells and elevated the sensitivity of intracellular calcium to 15 mM glucose. By contrast, WMS-1410 did not prevent the decline in glucose-stimulated insulin secretion occurring after glucolipotoxic culture. This lack of effect was due to a decrease in insulin content to 18% that obviously could not be compensated by the preservation of cell mass or the higher percentage of insulin release in relation to insulin content. In conclusion, the negative effects of permanent NMDAR activation were effectively counteracted by WMS-1410 as well as the apoptotic cell death induced by high glucose and lipid concentrations. Modulation of NMDARs containing the GluN2B subunit is suggested to preserve β cell mass during development of type 2 diabetes mellitus. SIGNIFICANCE STATEMENT: Addressing NMDA receptors containing the GluN2B subunit in pancreatic islet cells has the potential to protect the β cell mass that progressively declines during the development of type 2 diabetes. Furthermore, this study shows that harmful effects of permanent NMDAR activation can be effectively counteracted by the compound WMS-1410, a selective modulator for NMDARs containing the GluN2B subunit.

100 项与 WMS-1410 相关的药物交易

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