Sharples Christopher G V, Karig Gunter, Simpson Graham L, Spencer James A, Wright Emma, Millar Neil S, Wonnacott Susan, Gallagher Timothy
Department of Biology and Biochemistry, University of Bath, Bath BA2 7AY, UK.
J Med Chem. 2002 Jul 18;45(15):3235-45. doi: 10.1021/jm020814l.
(+/-)-UB-165 (1) is a potent neuronal nicotinic acetylcholine receptor (nAChR) ligand, which displays functional selectivity between nAChR subtypes. Using UB-165 as a lead structure, two classes of racemic ligands were synthesized and assessed in binding assays for three major nAChR subtypes (alpha4beta2, alpha3beta4, and alpha7). The first class of compounds comprises the three pyridine isomers 4-6, corresponding to the 3-, 2-, and 4-substituted pyridine isomers, respectively. Deschloro UB-165 (4) displayed a 2-3-fold decrease in affinity at alpha4beta2 and alpha3beta4 nAChR subtypes, as compared with (+/-)-UB-165, while at the alpha7 subtype a 31-fold increase in affinity was observed. At each of the nAChR subtypes, high affinity binding was dependent on the presence of a 3-substituted pyridine, and the other isomers, 5 and 6, resulted in marked decreases in binding affinities. The second class of compounds is based on replacing the pyridyl unit of 1 with a diazine moiety, giving pyridazine (7), pyrimidine (8), and pyrazine (9), which retain the "3-pyridyl" substructure. Modest reductions in binding affinity were observed for all of the diazine ligands at all nAChR subtypes, with the exception of 7, which retained potency comparable to that of 4 in binding to alpha7 nAChR. In functional assays at the alpha3beta4 nAChR, all analogues 4-9 were less potent, as compared with 1, and the rank order of functional potencies correlated with that of binding potencies. Computational studies indicate that the 3-substituted pyridine 4 and 2-substituted pyridine 5, as well as the diazine analogues 7-9, all conform to a distance-based pharmacophore model recently proposed for the alpha4beta2 receptor. However, the nicotinic potencies of these ligands vary considerably and because 5 lacks appreciable nicotinic activity, it is clear that further refinements of this model are necessary in order to describe adequately the structural and electronic demands associated with this nAChR subtype. This rational series of compounds based on UB-165 presents a systematic approach to defining subtype specific pharmacophores.
（±）-UB-165（1）是一种有效的神经元烟碱型乙酰胆碱受体（nAChR）配体，它在nAChR亚型之间表现出功能选择性。以UB-165作为先导结构，合成了两类外消旋配体，并针对三种主要的nAChR亚型（α4β2、α3β4和α7）进行了结合试验评估。第一类化合物包括三种吡啶异构体4 - 6，分别对应于3-、2-和4-取代的吡啶异构体。与（±）-UB-165相比，去氯UB-165（4）在α4β2和α3β4 nAChR亚型上的亲和力降低了2 - 3倍，而在α7亚型上观察到亲和力增加了31倍。在每种nAChR亚型上，高亲和力结合取决于3-取代吡啶的存在，而其他异构体5和6导致结合亲和力显著降低。第二类化合物是基于用二嗪部分取代1的吡啶单元，得到哒嗪（7）、嘧啶（8）和吡嗪（9），它们保留了“3-吡啶基”子结构。除了7在结合α7 nAChR时保留了与4相当的效力外，所有二嗪配体在所有nAChR亚型上的结合亲和力都有适度降低。在α3β4 nAChR的功能试验中，与1相比，所有类似物4 - 9的效力都较低，功能效力的排序与结合效力的排序相关。计算研究表明，3-取代吡啶4和2-取代吡啶5以及二嗪类似物7 - 9都符合最近为α4β2受体提出的基于距离的药效团模型。然而，这些配体的烟碱效力差异很大，并且由于5缺乏明显的烟碱活性，显然有必要进一步完善该模型，以便充分描述与该nAChR亚型相关的结构和电子需求。这种基于UB-165的合理系列化合物为定义亚型特异性药效团提供了一种系统方法。
