Combination of cyclohexane and piperazine based 魏-opioid receptor agonists: Synthesis and pharmacological evaluation of trans,trans-configured perhydroquinoxalines

详细信息    查看全文

• 作者：Christian Bourgeois ; Elena Werfel ; Dirk Schepmann ; Bernhard Wü ; nsch ; ^{wuensch@uni-muenster.de" class="auth_mail}
• 关键词：魏 Agonists ; Perhydroquinoxalines ; Desymmetrization ; Nitroaldol ; Conformational restriction ; Pseudochiral center ; Structure&ndash ; affinity relationships ; Selectivity
• 刊名：Bioorganic and Medicinal Chemistry
• 出版年：1 July 2014
• 年：2014
• 卷：22
• 期：13
• 页码：3316-3324
• 全文大小：641 K

文摘

Desymmetrization of the pseudochiral (2r)-configured cyclohexane-1,2,3-triamines 8 with dimethyl oxalate led to racemic aminoquinoxaline-2,3-diones 9. Selective introduction of the 魏 pharmacophoric structural elements pyrrolidine and 3,4-dichlorophenylacetamide with a two-carbon distance afforded conformationally restricted 魏 agonists 13–15 based on the quinoxaline ring system. In competitive radioligand receptor binding studies the benzylamine 13b, the secondary amine 14b, and the carbamate 15 displayed high 魏 receptor affinity. The K_i value of the lead compound derived methoxycarbonyl derivative 15 is 9.7 nM. However, the 魏 affinity of 15 is exceeded by 13b and 14b with a basic functional group instead of the methoxycarbonyl group in 1-position of the quinoxaline system. The chlorine atoms of the dichlorophenylacetyl residue are essential, since the corresponding phenylacetyl analogs show considerably reduced 魏 affinity. The potent 魏 ligands 13b, 14b and 15 are selective over the related 渭- and 未-opioid receptors, 蟽₁, 蟽₂ and NMDA receptors. In the [³⁵S]GTP纬S-binding assay 13b behaved as partial agonist with lower activity than U-69,593.