Pyrrolidine analogs of GZ-793A: synthesis and evaluation as inhibitors of the vesicular monoamine transporter-2 (VMAT2).
Bioorg Med Chem Lett
; 23(11): 3342-5, 2013 Jun 01.
Article
em En
| MEDLINE
| ID: mdl-23597792
ABSTRACT
Central heterocyclic ring size reduction from piperidinyl to pyrrolidinyl in the vesicular monoamine transporter-2 (VMAT2) inhibitor GZ-793A and its analogs resulted in novel N-propane-1,2(R)-diol analogs 11a-i. These compounds were evaluated for their affinity for the dihydrotetrabenazine (DTBZ) binding site on VMAT2 and for their ability to inhibit vesicular dopamine (DA) uptake. The 4-difluoromethoxyphenethyl analog 11f was the most potent inhibitor of [(3)H]-DTBZ binding (Ki=560 nM), with 15-fold greater affinity for this site than GZ-793A (Ki=8.29 µM). Analog 11f also showed similar potency of inhibition of [(3)H]-DA uptake into vesicles (Ki=45 nM) compared to that for GZ-793A (Ki=29 nM). Thus, 11f represents a new water-soluble inhibitor of VMAT function.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Pirrolidinas
/
Proteínas Vesiculares de Transporte de Monoamina
/
Lobelina
Limite:
Animals
Idioma:
En
Revista:
Bioorg Med Chem Lett
Assunto da revista:
BIOQUIMICA
/
QUIMICA
Ano de publicação:
2013
Tipo de documento:
Article
País de afiliação:
Estados Unidos