Design and synthesis of D-1 agonist/D-2 antagonist for treatment of schizophrenia

作者：Giovanni Andrew; Roehr Joachim; Dwyer Shannon; Neuenschwander Kent; Scotese Anthony; Moorcroft Neil D; Davis Larry; Gao Zhongli^*

来源：Bioorganic & Medicinal Chemistry Letters, 2013, 23(5): 1498-1501.

DOI：10.1016/j.bmcl.2012.12.046

• D-1 receptor (D1R) agonist and D-2 receptor (D2R) antagonist
• Tetrahydroisoquinoline
• Schizophrenia
• Nature product lead
• SAR and lead optimization

A series of tetrahydroisoquinolines were designed, synthesized and evaluated as the first non-natural product type of compounds with dual D-1 receptor (D1R) agonism and D-2 receptor (D2R) antagonism properties for treatment of schizophrenia. The initial SAR of the series was explored. The lead in the series, 3g, exhibited high affinity and good potency. Compound 3g displayed 95% of D1R occupancy (10 mg/kg, sc) and 75% of D2R occupancy (10 mg/kg, sc) in the striatum of male CD-1 mice. The series exhibited unique pharmacology and merit as tool compounds for target validation and future optimizations.

• 出版日期2013-3-1