Synthesis, pharmacological evaluation and docking analisys of novel anilidopiperidines

U okviru ove disertacije dizajnirano je 30 anilidopipredina, analoga jakog -opioidnog agonista i kliničkog analgetika fentanila. Razvijen je efikasan sintetički put za njihovo dobijanje, a sintetisana jedinjenja mogu se podeliti u dve serije. U okviru prve serije sintetisano je 13 novih analoga fentanila sa različitim azotnim grupama u položaju C3 piperidinskog prstena. Takođe je optimizovana sinteza dva prethodno sintetisana biciklična analoga fentanila. Jedinjenja prve serije predstavljaju prve poznate analoge fentanila sa azotnim grupama u položaju C3. U okviru druge serije sintetisano je 15 novih analoga fentanila, koji su u položaju N1 povezani sa pojedinim N-arilpiperazinima preko linearnih alkil mostova različitih dužina. Jedinjenja druge serije dizajnirana su da budu potencijalni heterobivalenti ligandi, jer sadrže anilidopiperidinsko jezgro fentanila kao -opioidnu agonističku farmakoforu, a N-arilpiperazin kao D2-dopaminergičku, agonističku farmakoforu. Analgetička aktivnost svih 30 jedinjenja ispitana je in vivo. Samo četiri jedinjenja, sva iz prve serije, pokazala su analgetičku aktivnost. Najaktivnije jedinjenje, oko 1,8 puta manje aktivno od fentanila, karakterišu brzo i kratko dejstvo analgetičkog efekta, pa se stoga može potencijalno iskoristiti u različitim farmacutskim formulacijama za tretman bola. Afinitet vezivanja jedinjenja druge serije za dopaminergčke D2 receptore ispitan je in vitro testovima kompeticije koristeći 3H spiperon kao radioaktivni ligand. Odsustvo analgetičke aktivnosti i slab afinitet vezivanja za dopaminergičke D2 receptore, ukazuje da jedinjenja druge serije ne mogu poslužiti kao heterobivalentni ligandi. Preliminarna doking analiza urađena je za jedinjenja koja su pokazala farmakološku aktivnost.This PhD thesis encompasses the design of 30 anilidopiperidines, as analogues of potent -opioid agonist and clinical analgesic, fentanyl. All compounds were prepared by the novel and effcient synthetic routes, and can be divided in two series. In the first series, 13 new analogues of fentanyl with various nitrogen groups in the C3 position of the piperidine ring were synthesized. In addition, the synthesis of two bicyclic analogues of fentanyl, previously synthesized by our group, was optimized. The compounds of the first series represent the first known fentanyl analogues possessing any nitrogen substituent at C3 position of the piperidine ring. The second series involved preparation of 15 new compounds consisting of fentanyl moiety and several arylpiperazine groups joined by the respective secondary nitrogens, via the variable-length alkyl linkers. The compounds were designed to be potential heterobivalent ligands, since they include both the fentanyl core, as the -opioid agonist pharmacophore, and N-arylpiperazine moiety as the D2-dopaminergic agonist pharmacophore. The analgesic activity of 30 compounds was tested in vivo. Only four compounds, all from the first series, showed analgesic activity. The most potent of them was 1.8 times less potent analgesic than fentanyl, with fast onset and short duration of analgesic effect, which makes this compound potentially suitable for different pharmacological formulation in the pain treatment. Binding affinity of the compounds of the second series towards dopaminergic D2 receptors was determined by in vitro competitive assay, using 3H spiperon as radioactive ligand. Compounds of the second series were found to be inactive as analgesics and with low affinity towards dopaminergic D2 receptors. Therefore, the compounds do not represent heterobivalent ligands. Preliminary docking analysis was performed for the pharmacologically active compounds