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Bioorg Med Chem Lett. 2013 Mar 1;23(5):1498-501. doi: 10.1016/j.bmcl.2012.12.046. Epub 2012 Dec 21.

Design and synthesis of D₁ agonist/D₂ antagonist for treatment of schizophrenia.

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1
Translational Medicine, 55 Corporate Drive, Sanofi US, 1041 Route 202-206 North, Bridgewater, NJ 08807, United States.

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.

PMID:
23333208
DOI:
10.1016/j.bmcl.2012.12.046
[Indexed for MEDLINE]
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