Synthesis of Novel Nicotinic Ligands with Multimodal Action: Targeting Acetylcholine alpha 4 beta 2, 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 alpha 4 beta 2 nAChR, h-SERT and h-DAT. SERT experiments showed not radioligand [H-3]-paroxetine displacement, but rather an increase in the radioligand binding percentage at the central binding site was observed. Compound 20 showed K-i values of 1.008 +/- 0.230 mu M for h-DAT and 0.031 +/- 0.006 mu M for alpha 4 beta 2 nAChR, and [H-3]-paroxetine binding of 191.50% in h-SERT displacement studies, being the only compound displaying triple affinity. Compound 21 displayed K-i values of 0.113 +/- 0.037 mu M for alpha 4 beta 2 nAChR and 0.075 +/- 0.009 mu M for h-DAT acting as a dual ligand. Molecular docking studies on homology models of alpha 4 beta 2 nAChR, h-DAT and h-SERT suggested potential interactions among the compounds and agonist binding site at the alpha 4/beta 2 subunit interfaces of alpha 4 beta 2 nAChR, central binding site of h-DAT and allosteric modulator effect in h-SERT.
|Título según WOS:||Synthesis of Novel Nicotinic Ligands with Multimodal Action: Targeting Acetylcholine alpha 4 beta 2, Dopamine and Serotonin Transporters|
|Título según SCOPUS:||Synthesis of novel nicotinic ligands with multimodal action: Targeting Acetylcholine ?4?2, Dopamine and Serotonin Transporters|
|Título de la Revista:||MOLECULES|
|Fecha de publicación:||2019|