Ivy Carroll F, Ma Wei, Navarro Hernán A, Abraham Philip, Wolckenhauer Scott A, Damaj M I, Martin Billy R
Chemistry and Life Sciences, Research Triangle Institute, Research Triangle Park, NC 27709, USA.
Bioorg Med Chem. 2007 Jan 15;15(2):678-85. doi: 10.1016/j.bmc.2006.10.061. Epub 2006 Nov 1.
A series of methyllycaconitine (1a, MLA) analogs was synthesized where the (S)-2-methylsuccinimidobenzoyl group in MLA was replaced with a (R)-2-methyl, 2,2-dimethyl-, 2,3-dimethyl, 2-phenyl-, and 2-cyclohexylsuccinimidobenzoyl (1b-f) group. The analogs 1b-f were evaluated for their inhibition of [(125)I]iodo-MLA binding at rat brain alpha7 nicotinic acetylcholine receptors (nAChR). In order to determine selectivity, MLA and the analogs 1b-f were evaluated for inhibition of binding to rat brain alpha,beta nAChR using [(3)H]epibatidine. At the alpha7 nAChR, MLA showed a K(i) value of 0.87 nM, analogs 1b-e possessed K(i) values of 1.67-2.16 nM, and 1f showed a K(i) value of 26.8 nM. Surprisingly, the analog 1e containing the large phenyl substituent (K(i)=1.67 nM) possessed the highest affinity. None of the compounds possessed appreciable affinity for alpha,beta nAChRs. MLA antagonized nicotine-induced seizures with an AD(50)=2 mg/kg. None of the MLA analogs were as potent as MLA in this assay. MLA and all of the MLA analogs, with the exception of 1b, antagonized nicotine's antinociceptive effects in the tail-flick assay. Compound 1c (K(i)=1.78 nM at alpha7 nAChR) with an AD(50) value of 1.8 mg/kg was 6.7 times more potent than MLA (AD(50)=12 mg/kg) in antagonizing nicotine's antinociceptive effects but was 5-fold less potent than MLA in blocking nicotine-induced seizures. Since MLA has been reported to show neuroprotection against beta-amyloid(1-42), these new analogs which have high alpha7 nAChR affinity and good selectivity relative to alpha,beta nAChRs will be useful biological tools for studying the effects of alpha7 nAChR antagonist and neuroprotection.
合成了一系列甲基lycaconitine（1a，MLA）类似物，其中MLA中的（S）-2-甲基琥珀酰亚胺苯甲酰基被（R）-2-甲基、2,2-二甲基、2,3-二甲基、2-苯基和2-环己基琥珀酰亚胺苯甲酰基（1b - f）取代。评估了类似物1b - f对大鼠脑α7烟碱型乙酰胆碱受体（nAChR）上[(125)I]碘代-MLA结合的抑制作用。为了确定选择性，使用[(3)H]依博加碱评估了MLA和类似物1b - f对大鼠脑α、β nAChR结合的抑制作用。在α7 nAChR上，MLA的K(i)值为0.87 nM，类似物1b - e的K(i)值为1.67 - 2.16 nM，1f的K(i)值为26.8 nM。令人惊讶的是，含有大的苯基取代基的类似物1e（K(i)=1.67 nM）具有最高的亲和力。这些化合物对α、β nAChRs均无明显亲和力。MLA拮抗尼古丁诱导的惊厥，AD(50)=2 mg/kg。在该试验中，没有一种MLA类似物与MLA一样有效。MLA和除1b外的所有MLA类似物在甩尾试验中拮抗尼古丁的抗伤害感受作用。化合物1c（在α7 nAChR处的K(i)=1.78 nM）的AD(50)值为1.8 mg/kg，在拮抗尼古丁的抗伤害感受作用方面比MLA（AD(50)=12 mg/kg）强6.7倍，但在阻断尼古丁诱导的惊厥方面比MLA弱5倍。由于据报道MLA对β-淀粉样蛋白(1 - 42)具有神经保护作用，这些相对于α、β nAChRs具有高α7 nAChR亲和力和良好选择性的新类似物将是研究α7 nAChR拮抗剂作用和神经保护作用的有用生物学工具。
