Jans Alzate Morales Química computacional, reactividad enzimática e ingeniería de proteínas, interacción ligando-proteína.

Designing chemical poly-bullets for nicotinic acetylcholine receptors and monoamine transporters (SERT, NET and DAT). A poly-pharmacology approach to understand the nicotine addiction and withdrawal syndrome mediated by multiple receptor targets

Periodo 2015 a 2019
Posición Associate researcher
Concurso FONDECYT Regular
Identificador No. 1150615

Nicotine, the main alkaloid from the tobacco plants is a potent psychoactive drug that induces euphoria and addiction. This alkaloid binds to a particular class of ligand-gated ion channels, named nicotinic acetylcholine receptors (nAChRs). nAChRs are widely distributed in the central nervous system and modulate a collection of different functions including attention, cognition, mood states, reward and addiction. Nicotine addiction normally involves a reinforcement behavior and influences reward and withdrawal processes. Mesocorticolimbic dopamine system plays an important role in the acquisition of behaviors that induce reward and addiction by psycho-stimulant drugs, including nicotine, whilst the withdrawal symptoms of smoking cessation could be mediated by nAChRs in the habenular complex and its target the interpeduncular nucleus. The unpleasant effects produced during the withdrawal syndrome after cessation of nicotine are generally treated by nicotine replacement therapies including nicotine patch, pills and gums, and nicotinic ligands. In addition, smoking cessation has been associated with anxiety and depressive states. In recent years, researchers have serendipitously discovered that antidepressants bind to nAChRs with relatively high affinities, but in an alosteric antagonist manner. Antidepressants act mainly inhibiting the monoaminergic reuptake by blocking the corresponding neurotransmitter transporter (SERT, DAT, NET). Tricyclic antidepressants, such as imipramine or amitriptyline, selective serotonin reuptake inhibitors (SSRIs) (flouxetine, sertraline), the serotonin-norepinephrine reuptake inhibitor venlafaxine, the dopamine/norepinephrine reuptake blocker bupropion and the selective norepinephrine reuptake inhibitor reboxetine, mainly used by treatment of depression and mood disorder, display functional inhibition of nAChR agonist-evoked currents. There are many evidences supporting the idea that molecules that bind simultaneously to different targets could have better therapeutic profiles and less side effects than selective ligands. In this way, we propose that the design of competitive antagonists for nAChRs that combine structural features with SERT, DAT and/or NET blockers might be a good strategy to find a new class of drugs that, through a multiple mechanism, contribute to smoke cessation and decrease symptoms of withdrawal syndrome such as anxiety and depression. Our pharmacological approach will be: a fast binding screening for SERT, DAT, NET and α4β2 and α7 nAChRs using clonal cell lines; the compounds with the highest affinities will be tested for their ability to inhibit the DA, 5-HT and NE uptake in rat synaptosomes and the functional activity over α4β2 and α7 nAChR acetylcholine-evoked currents and DA release will be performed. Molecular modelling approach will be used to understand the binding mode of our compounds.
We expect that our designed molecules will unveil the association between nicotinic receptor and monoamine transporter and will contribute to understand the pharmacological mechanisms involved in nicotine addiction, reward and withdrawal.