High-affinity, selective σ ligands of the 1,2,3,4-tetrahydro-1,4'-silaspiro[naphthalene-1,4'-piperidine] type: syntheses, structures, and pharmacological properties.
ChemMedChem
; 7(3): 523-32, 2012 Mar 05.
Article
em En
| MEDLINE
| ID: mdl-22076883
ABSTRACT
The 1'-organyl-1,2,3,4-tetrahydrospiro[naphthalene-1,4'-piperidine] derivatives 1 a-4 a [for which organyl=benzyl (1 a), 4-methoxybenzyl (2 a), 2-phenylethyl (3 a), or 3-methylbut-2-enyl (4 a)] are high-affinity, selective σ1 ligands. The corresponding sila-analogues 1 b-4 b (replacement of the carbon spirocenter with a silicon atom) were synthesized in multistep syntheses, starting from dichlorodivinylsilane, and were isolated as the hydrochlorides 1 bâ
HCl-4 bâ
HCl. Compounds 1 aâ
HCl-4 aâ
HCl and 1 bâ
HCl-4 bâ
HCl were structurally characterized by NMR spectroscopy (¹H, ¹³C, ²9Si) in solution, and the C/Si analogues 3 aâ
HCl and 3 bâ
HCl were studied by single-crystal X-ray diffraction. These structural investigations were complemented by computational studies. The σ1 and σ2 receptor affinities of the C/Si pairs 1 a/1 b-4 a/4 b were studied with radioligand binding assays. The σ1 receptor affinity of the silicon compounds 1 b-4 b is slightly higher than that of the corresponding carbon analogues 1 a-4 a. Because affinity for the σ2 receptor is decreased by the C/Si exchange, the σ1/σ2 selectivity of the silicon compounds is considerably improved, indicating that the CâSi switch strategy is a powerful tool for modulating both pharmacological potency and selectivity.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Piperidinas
/
Silício
/
Carbono
/
Receptores sigma
/
Fármacos Neuroprotetores
/
Naftalenos
Limite:
Animals
/
Humans
Idioma:
En
Revista:
ChemMedChem
Ano de publicação:
2012
Tipo de documento:
Article