Novel High-Affinity and Selective Biaromatic 4-Substituted γ-Hydroxybutyric Acid (GHB) Analogues as GHB Ligands: Design, Synthesis, and Binding Studies

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• 作者：Signe Hø ; g ; Petrine Wellendorph ; Birgitte Nielsen ; Karla Frydenvang ; Ivar F. Dahl ; Hans Bruner-Osborne ; Lotte Brehm ; Bente Frø ; lund ; Rasmus P. Clausen
• 刊名：Journal of Medicinal Chemistry
• 出版年：2008
• 出版时间：December 25, 2008
• 年：2008
• 卷：51
• 期：24
• 页码：8088-8095
• 全文大小：207K
• 年卷期：v.51,no.24(December 25, 2008)
• ISSN：1520-4804

文摘

γ-Hydroxybutyrate (GHB) is a metabolite of γ-aminobutyric acid (GABA) and has been proposed to function as a neurotransmitter or neuromodulator. GHB is used in the treatment of narcolepsy and is a drug of abuse. GHB binds to both GABA_B receptors and specific high-affinity GHB sites in brain, of which the latter have not been linked unequivocally to function, but are speculated to be GHB receptors. In this study, a series of biaromatic 4-substituted GHB analogues, including 4′-phenethylphenyl, 4′-styrylphenyl, and 4′-benzyloxyphenyl GHB analogues, were synthesized and characterized pharmacologically in a [³H](E,RS)-(6,7,8,9-tetrahydro-5-hydroxy-5H-benzocyclohept-6-ylidene)acetic acid ([³H]NCS-382) binding assay and in GABA_A and GABA_B receptor binding assays. The compounds were selective for the high-affinity GHB binding sites and several displayed K_i values below 100 nM. The affinity of the 4-[4′-(2-iodobenzyloxy)phenyl] GHB analogue 17b was shown to reside predominantly with the R-enantiomer (K_i = 22 nM), which has higher affinity than previously reported GHB ligands.