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1.
Molecules ; 25(13)2020 Jun 30.
Artigo em Inglês | MEDLINE | ID: mdl-32630020

RESUMO

Zebrafish is becoming a popular animal model in neuropharmacology and drug discovery, mainly due to its ease of handling and low costs involved in maintenance and experimental work. This animal displays a series of complex behaviours that makes it useful for assessing the effects of psychoactive drugs. Here, adult zebrafish were used for assessment of the anxiolytic and anti-addictive properties of UFR2709, a nicotinic receptor (nAChR) antagonist, using two behavioural paradigms to test for addiction, the novel tank diving test to assess anxiety and the conditioned place preference (CPP). Furthermore, the expression of nAChR subunits α4 and α7 was measured in the zebrafish brain. The results show that UFR2709 exhibits an anxiolytic effect on zebrafish and blocks the effect evoked by nicotine on CPP. Moreover, UFR2709 significantly decreased the expression of α4 nicotinic receptor subunit. This indicates that UFR2709 might be a useful drug for the treatment of nicotine addiction.


Assuntos
Ansiolíticos/farmacologia , Ansiedade/prevenção & controle , Comportamento Animal/efeitos dos fármacos , Benzoatos/farmacologia , Nicotina/antagonistas & inibidores , Antagonistas Nicotínicos/farmacologia , Pirrolidinas/farmacologia , Receptores Nicotínicos/metabolismo , Recompensa , Animais , Ansiedade/induzido quimicamente , Modelos Animais de Doenças , Nicotina/administração & dosagem , Receptores Nicotínicos/genética , Natação , Peixe-Zebra
2.
Molecules ; 24(20)2019 Oct 22.
Artigo em Inglês | MEDLINE | ID: mdl-31652614

RESUMO

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.


Assuntos
Acetilcolina/análogos & derivados , Proteínas da Membrana Plasmática de Transporte de Dopamina/química , Nicotina/análogos & derivados , Receptores Nicotínicos/química , Proteínas da Membrana Plasmática de Transporte de Serotonina/química , Acetilcolina/agonistas , Acetilcolina/síntese química , Acetilcolina/química , Regulação Alostérica , Sítios de Ligação , Dopamina/química , Agonistas de Dopamina/química , Proteínas da Membrana Plasmática de Transporte de Dopamina/agonistas , Ésteres/química , Células HEK293 , Humanos , Ligantes , Simulação de Acoplamento Molecular , Nicotina/agonistas , Nicotina/síntese química , Nicotina/química , Agonistas Nicotínicos/química , Pirrolidinas/química , Ensaio Radioligante , Proteínas da Membrana Plasmática de Transporte de Serotonina/agonistas , Relação Estrutura-Atividade
3.
Molecules ; 24(15)2019 Jul 24.
Artigo em Inglês | MEDLINE | ID: mdl-31344816

RESUMO

Neuronal α4ß2 nicotinic acetylcholine receptors (nAChRs) are ligand-gated ion channels (LGIC) that have been implicated in nicotine addiction, reward, cognition, pain disorders, anxiety, and depression. Nicotine has been widely used as a template for the synthesis of ligands that prefer α4ß2 nAChRs subtypes. The most important therapeutic use for α4ß2 nAChRs is as replacement therapy for smoking cessation and withdrawal and the most successful therapeutic ligands are partial agonists. In this case, we use the N-methylpyrrolidine moiety of nicotine to design and synthesize new α4ß2 nicotinic derivatives, coupling the pyrrolidine moiety to an aromatic group by introducing an ether-bonded functionality. Meta-substituted phenolic derivatives were used for these goals. Radioligand binding assays were performed on clonal cell lines of hα4ß2 nAChR and two electrode voltage-clamp experiments were used for functional assays. Molecular docking was performed in the open state of the nAChR in order to rationalize the agonist activity shown by our compounds.


Assuntos
Nicotina/química , Nicotina/farmacologia , Agonistas Nicotínicos/química , Agonistas Nicotínicos/farmacologia , Receptores Nicotínicos/química , Ligação Competitiva , Relação Dose-Resposta a Droga , Humanos , Cinética , Conformação Molecular , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Estrutura Molecular , Nicotina/análogos & derivados , Ligação Proteica , Relação Estrutura-Atividade
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