Saavedra Oscar M, Karila Delphine, Brossard Dominique, Rojas Anne, Dupuis Delphine, Gohier Arnaud, Mannoury la Cour Clotilde, Millan Mark J, Ortuno Jean-Claude, Hanessian Stephen
Université de Montréal, Department of Chemistry, PO Box 6128, Station, Centre-ville, Montréal, Que. H3C 3J7, Canada.
Chemistry Pole of Expertise, Institut de Recherches Servier, 3 rue de la République, 92150 Suresnes, France.
Bioorg Med Chem. 2017 Jan 1;25(1):38-52. doi: 10.1016/j.bmc.2016.10.010. Epub 2016 Oct 12.
All clinically-used antipsychotics display similar affinity for both D (D2R) and D (D3R) receptors, and they likewise act as 5-HT receptor antagonists. They provide therapeutic benefit for positive symptoms, but no marked or consistent improvement in neurocognitive, social cognitive or negative symptoms. Since blockade of D and 5-HT (5-HT6R) receptors enhances neurocognition and social cognition, and potentially improves negative symptoms, a promising approach for improved treatment for schizophrenia would be to develop drugs that preferentially act at D3R versus D2R and likewise recognize 5-HT6R. Starting from the high affinity 5-HT6R ligands I and II, we identified compounds 11a and 14b that behave as 5-HT6R ligands with significant selectivity for D3R over D2R.
所有临床使用的抗精神病药物对D（D2R）和D（D3R）受体都表现出相似的亲和力，并且它们同样作为5-羟色胺受体拮抗剂发挥作用。它们对阳性症状有治疗益处，但对神经认知、社会认知或阴性症状没有显著或持续的改善。由于阻断D和5-羟色胺（5-HT6R）受体可增强神经认知和社会认知，并可能改善阴性症状，因此开发优先作用于D3R而非D2R并同样识别5-HT6R的药物将是改善精神分裂症治疗的一种有前景的方法。从高亲和力的5-HT6R配体I和II开始，我们鉴定出化合物11a和14b，它们作为5-HT6R配体，对D3R的选择性显著高于D2R。
