Synthesis of Novel Nicotinic Ligands with Multimodal Action: Targeting Acetylcholine α4ß2, Dopamine and Serotonin Transporters.
Molecules
; 24(20)2019 Oct 22.
Article
en En
| MEDLINE
| ID: mdl-31652614
ABSTRACT
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.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Acetilcolina
/
Receptores Nicotínicos
/
Proteínas de Transporte de Dopamina a través de la Membrana Plasmática
/
Proteínas de Transporte de Serotonina en la Membrana Plasmática
/
Nicotina
Límite:
Humans
Idioma:
En
Revista:
Molecules
Asunto de la revista:
BIOLOGIA
Año:
2019
Tipo del documento:
Article
País de afiliación:
Chile