Unlocking Nicotinic Selectivity via Direct C-H Functionalization of (-)-Cytisine
Unlocking Nicotinic Selectivity via Direct C-H Functionalization of (-)-Cytisine
复制标题
DOI：
10.1016/j.chempr.2018.05.007
复制
发表时间：
2018-07-12
期刊：
影响因子：
23.5
通讯作者：
Gallagher, Timothy
中科院分区：
文献类型：
--
作者：
Campello, Hugo Rego;Del Villar, Silvia G.;Gallagher, Timothy
分化尼古丁乙酰胆碱受体（nAChR）以靶向高亲和性尼古丁α 4 β 2亚型是开发有效成瘾治疗的主要挑战。虽然胞氨酸1和伐尼克兰2（目前的戒烟药物）是α 4 β 2的部分激动剂，但这些药物对α 7 nAChR亚型表现出完全激动作用。通过ir催化的C. H活化对(-)-cytisine进行位点特异性修饰，可以进入C（10）变异6-10、13、14、17、20和22，对接研究表明，C（10）取代靶向受体结合位点的互补区域，介导亚型分化。C（10）修饰的胱氨酸配体保留了对α 4 β 2 nAChR的亲和力，并且是部分激动剂，与α 4 β 2和α 7亚型相比，对α 4 β 2表现出增强的选择性，关键是，在α 7表现出可忽略不计的活性。分子动力学模拟将C（10）片段与受体亚型分化联系起来；确定了直接结合位点以外的关键残基，并表征了导致这些关键差异的分子水平构象行为。
Differentiating nicotinic acetylcholine receptors (nAChR) to target the highaffinity nicotine alpha 4 beta 2 subtype is amajor challenge in developing effective addiction therapies. Although cytisine 1 and varenicline 2 (current smoking-cessation agents) are partial agonists of alpha 4 beta 2, these drugs display full agonism at the alpha 7 nAChR subtype. Site-specific modification of (-)-cytisine via Ir-catalyzed C. H activation provides access to C(10) variants 6-10, 13, 14, 17, 20, and 22, and docking studies reveal that C(10) substitution targets the complementary region of the receptor binding site, mediating subtype differentiation. C(10)modified cytisine ligands retain affinity for alpha 4 beta 2 nAChR and are partial agonists, show enhanced selectivity for alpha 4 beta 2 versus both alpha 4 beta 2 and alpha 7 subtypes, and critically, display negligible activity at alpha 7. Molecular dynamics simulations link the C(10) moiety to receptor subtype differentiation; key residues beyond the immediate binding site are identified, and molecular-level conformational behavior responsible for these crucial differences is characterized.