A series of tetrahydroisoquinolines were designed, synthesized and evaluated as the first non-natural product type of compounds with dual D(1) receptor (D(1)R) agonism and D(2) receptor (D(2)R) 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 D(1)R occupancy (10 mg/kg, sc) and 75% of D(2)R 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.
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