Modification of the anabaseine pyridine nucleus allows achieving binding and functional selectivity for the α3ß4 nicotinic acetylcholine receptor subtype.
Eur J Med Chem
; 108: 392-405, 2016 Jan 27.
Article
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| MEDLINE
| ID: mdl-26706350
ABSTRACT
We report the design, synthesis and pharmacological screening of a group of analogues of anabaseine 2, a naturally occurring unselective nicotinic agonist. The novel nAChR ligands 5-15 were planned following a molecular modeling analysis which suggested the replacement of the pyridine ring of 2 with a 3-substituted benzene ring as a means to gain selectivity for the α3ß4 nAChR subtype. Overall, from binding experiments, the synthesized compounds showed high values of α3ß4 affinity and α3ß4 vs α4ß2 selectivity, although they poorly discriminated the homomeric α7 subtype. The three analogues 6, 12 and 13 were also evaluated in electrophysiological assays, and 12 [6-(3-iodophenyl)-2,3,4,5-tetrahydropyridine] emerged as a rather interesting nicotinic ligand. Indeed, in addition to a noteworthy affinity (Ki = 4.7 nM) for the α3ß4 subtype and to an excellent α3ß4 vs α4ß2 subtype selectivity (806-fold), compound 12 selectively activated the α3ß4 nAChR (EC50 = 7.4 µM) while eliciting a negligible response at the α7 subtype and no effect at the α4ß2 subtype.
Palabras clave
Texto completo:
1
Bases de datos:
MEDLINE
Asunto principal:
Piridinas
/
Receptores Nicotínicos
/
Anabasina
Límite:
Humans
Idioma:
En
Revista:
Eur J Med Chem
Año:
2016
Tipo del documento:
Article
País de afiliación:
Italia