Synthesis of Novel Nicotinic Ligands with Multimodal Action: Targeting Acetylcholine α4ß2, Dopamine and Serotonin Transporters.

Nicotinic acetylcholine receptors (nAChRs), serotonin transporters (SERT) and dopamine transporters (DAT) represent targets for the development of novel nicotinic derivatives acting as multiligands associated with different health conditions, such as depressive, anxiety and addiction disorders. In the present work, a series of functionalized esters structurally related to acetylcholine and nicotine were synthesized and pharmacologically assayed with respect to these targets. The synthesized compounds were studied in radioligand binding assays at α4ß2 nAChR, h-SERT and h-DAT. SERT experiments showed not radioligand [3H]-paroxetine displacement, but rather an increase in the radioligand binding percentage at the central binding site was observed. Compound 20 showed Ki values of 1.008 ± 0.230 µM for h-DAT and 0.031 ± 0.006 µM for α4ß2 nAChR, and [3H]-paroxetine binding of 191.50% in h-SERT displacement studies, being the only compound displaying triple affinity. Compound 21 displayed Ki values of 0.113 ± 0.037 µM for α4ß2 nAChR and 0.075 ± 0.009 µM for h-DAT acting as a dual ligand. Molecular docking studies on homology models of α4ß2 nAChR, h-DAT and h-SERT suggested potential interactions among the compounds and agonist binding site at the α4/ß2 subunit interfaces of α4ß2 nAChR, central binding site of h-DAT and allosteric modulator effect in h-SERT.

Effect of pressurized hot water extraction on antioxidants from grape pomace before and after enological fermentation.

Grape pomace was extracted with pressurized hot water at laboratory scale before and after fermentation to explore the effects of fermentation and extraction temperature (50-200 °C) and time (5 and 30 min) on total extracted antioxidant levels and activity and to determine the content and recovery efficiency of main grape polyphenols, anthocyanins, and tannins. Fermented pomace yielded more total antioxidants (TAs), antioxidant activity, and tannins, than unfermented pomace but fewer anthocyanins. Elevating the extraction temperature increased TA extraction and antioxidant activity. Maximum anthocyanin extraction yields were achieved at 100 °C and at 150 °C for tannins and tannin-anthocyanin adducts. Using higher temperatures and longer extraction times resulted in a sharp decrease of polyphenol extraction yield. Relevant proanthocyanidin amounts were extracted only at 50 and 100 °C. Finally, TA recovery and activity were not directly related to the main polyphenol content when performing pressurized hot water grape pomace extraction.