Design, Sustainable Synthesis and Biological Evaluation of a Novel Dual α2A/5-HT7 Receptor Antagonist with Antidepressant-Like Properties.

The complex pathophysiology of depression, together with the limits of currently available antidepressants, has resulted in the continuous quest for alternative therapeutic strategies. Numerous findings suggest that pharmacological blockade of α2-adrenoceptor might be beneficial for the treatment of depressive symptoms by increasing both norepinephrine and serotonin levels in certain brain areas. Moreover, the antidepressant properties of 5-HT7 receptor antagonists have been widely demonstrated in a large set of animal models. Considering the potential therapeutic advantages in targeting both α2-adrenoceptors and 5-HT7 receptors, we designed a small series of arylsulfonamide derivatives of (dihydrobenzofuranoxy)ethyl piperidines as dually active ligands. Following green chemistry principles, the designed compounds were synthesized entirely using a sustainable mechanochemical approach. The identified compound 8 behaved as a potent α2A/5-HT7 receptor antagonist and displayed moderate-to-high selectivity over α1-adrenoceptor subtypes and selected serotonin and dopaminergic receptors. Finally, compound 8 improved performance of mice in the forced swim test, displaying similar potency to the reference drug mirtazapine.

Stereocontrolled synthesis of oleanolic saponin ladyginoside A isolated from Ladyginia bucharica.

Efficient stereocontrolled synthesis of ladyginoside A isolated from Ladyginia bucharica is described. The presented methodology bases on the ß-selective glycosylation to construct oleanate-3-O-ß-glycoside from selectively protected d-cellobiose comprising desired ß-linkage in carbohydrate unit. By using this procedure, dimethyl ester of ladyginoside A (1) (methyl oleanate 3-O-(ß-d-glucopyranosyl)-(1 → 4)-ß-d-glucuronide methyl ester) was obtained in 16% overall yield. Elaborated synthesis is also demonstrated as useful methodology en route to saponin 2 with additional glucose unit, namely 3-O-[ß-d-glucopyranosyl-(1 → 4)-ß-d-glucuronide] oleanolic acid 28-O-ß-d-glucopyranosyl ester.