title: Design and synthesis of D₁ agonist/D₂ antagonist for treatment of schizophrenia.
abstract: 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.
authors: Translational Medicine, 55 Corporate Drive, Sanofi US, 1041 Route 202-206 North, Bridgewater, NJ 08807, United States.
authors: Andrew
authors: A
authors: Giovanni
authors: Joachim
authors: J
authors: Roehr
authors: Shannon
authors: S
authors: Dwyer
authors: Kent
authors: K
authors: Neuenschwander
authors: Anthony
authors: A
authors: Scotese
authors: Neil D
authors: ND
authors: Moorcroft
authors: Larry
authors: L
authors: Davis
authors: Zhongli
authors: Z
authors: Gao
mesh_terms: D000818:Animals; D065127:Dopamine D2 Receptor Antagonists; D015195:Drug Design; D008297:Male; D051379:Mice; D017447:Receptors, Dopamine D1 / Q000819:agonists* / Q000378:metabolism; D017448:Receptors, Dopamine D2 / Q000378:metabolism; D012559:Schizophrenia / Q000188:drug therapy* / Q000473:pathology; D013329:Structure-Activity Relationship; D044005:Tetrahydroisoquinolines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*
chemical_list: D065127:Dopamine D2 Receptor Antagonists; D017447:Receptors, Dopamine D1; D017448:Receptors, Dopamine D2; D044005:Tetrahydroisoquinolines