本项课题以新型机制的抗精神病药靶ɑ2C肾上腺素受体（ɑ2C-AR）拮抗活性为导向，以具有临床发展前景的新型选择性ɑ2C-AR拮抗剂ORM-10291为切入点，运用合理的药物分子设计思想，设计了新颖的咪唑并[1,2-a] 吡啶类化合物；将申请人自主开发的咪唑并[1,2-a]吡啶串联反应、手性亚酰胺的不对称ɑ-烷基化反应构建手性季碳片段等合成方法拓展到ORM-10291和目标物的不对称合成中；评价该类化合物针对ɑ2A、ɑ2B和ɑ2C-AR三种亚型的结合与拮抗功能活性；对优选的化合物在体外血脑屏障模型上评价其过膜效果。期望通过上述研究，建立首个不对称合成ORM-10291的方法；开发一类新颖的可透过血脑屏障的选择性ɑ2C-AR拮抗剂；建立该类化合物的ɑ2C-AR选择性拮抗作用的药效团模型,从分子水平上初步阐明该类化合物拮抗ɑ2C-AR功能的结构要素。

Directed by alpha-2C adrenoceptor antagonism related to a new mechanism for the treatment of psychopathy,this project will focus on the asymmetric synthesis of ORM-10921, a novel selective ɑ2C-AR antagonist displaying antipsychopatic perspective in the Phase II study,and then on asymmetric synthesis of new imdazo[1,2-a]pyridine analogues designed by the rational drug design idea. Through our own synthetic methods of tandem reaction for imidazo[1,2-a]pyridines and ɑ-alkylation of chiral imdines, ORM-10921 and the designed compounds will be synthesized, and then be evaluated in vitro for ɑ2A, ɑ2B or ɑ2C-ARs including binding assay, functional activity assay and preliminary penetrant assay on the Blood-Brain-Barrier model. Based on the above work, a novel asymmetric synthetic method for ORM-10921 would be established; novel selectve and permeable ɑ2C-AR antagonists would be discovered; and the correponding pharmacophore model could be explored in order to elucidate the ligand structural elements for ɑ2C-AR antagonism funtion.