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Synthesis and biological evaluation of a new series of hexahydro-2H-pyrano[3,2-c]quinolines as novel selective σ1 receptor ligands.

Abstract：

:The synthesis and pharmacological activity of a new series of hexahydro-2H-pyrano[3,2-c]quinoline derivatives as potent σ1 receptor (σ1R) ligands are reported. This family, which does not contain the highly basic amino group usually present in other σ1R ligands, showed high selectivity over the σ2 receptor (σ2R). The activity was shown to reside in only one of the four possible diastereoisomers, which exhibited a perfect match with known σ1R pharmacophores. A hit to lead program based on a high-throughput screening hit (8a) led to the identification of compound 32c, with substantially improved activity and physicochemical properties. Compound 32c also exhibited a good ADMET (absorption, distribution, metabolism, excretion, toxicity) profile and was identified as a σ1R antagonist on the basis of its analgesic activity in the mouse capsaicin and formalin models of neurogenic pain.

journal_name

J Med Chem

journal_title

Journal of medicinal chemistry

authors

Díaz JL,Christmann U,Fernández A,Luengo M,Bordas M,Enrech R,Carro M,Pascual R,Burgueño J,Merlos M,Benet-Buchholz J,Cerón-Bertran J,Ramírez J,Reinoso RF,Fernández de Henestrosa AR,Vela JM,Almansa C

doi

10.1021/jm400181k

subject

Has Abstract

pub_date

2013-05-09 00:00:00

pages

3656-65

issue

9

eissn

0022-2623

issn

1520-4804

journal_volume

56

pub_type

杂志文章

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