Synthesis and Biological Evaluation of a New Series of Hexahydro-2H-pyrano[3,2-c]quinolines as Novel Selective 蟽1 Receptor Ligands

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• 作者：Jos茅 Luis D铆az ; Ute Christmann ; Ariadna Fern谩ndez ; M贸nica Luengo ; Magda Bordas ; Raquel Enrech ; M贸nica Carro ; Rosalia Pascual ; Javier Burgue帽o ; Manuel Merlos ; Jordi Benet-Buchholz ; Jordi Cer贸n-Bertran ; Jes煤s Ram铆rez ; Raquel F. Reinoso ; Antonio R. Fern谩ndez de Henestrosa ; Jos茅 Miguel Vela ; Carmen Almansa
• 刊名：Journal of Medicinal Chemistry
• 出版年：2013
• 出版时间：May 9, 2013
• 年：2013
• 卷：56
• 期：9
• 页码：3656-3665
• 全文大小：386K
• 年卷期：v.56,no.9(May 9, 2013)
• ISSN：1520-4804

文摘

The synthesis and pharmacological activity of a new series of hexahydro-2H-pyrano[3,2-c]quinoline derivatives as potent 蟽₁ receptor (蟽₁R) ligands are reported. This family, which does not contain the highly basic amino group usually present in other 蟽₁R ligands, showed high selectivity over the 蟽₂ receptor (蟽₂R). The activity was shown to reside in only one of the four possible diastereoisomers, which exhibited a perfect match with known 蟽₁R 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 蟽₁R antagonist on the basis of its analgesic activity in the mouse capsaicin and formalin models of neurogenic pain.