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: Andrew Giovanni, Joachim Roehr, Shannon Dwyer, Kent Neuenschwander, Anthony Scotese, Neil D Moorcroft, Larry Davis, Zhongli Gao
• Journal: Bioorganic & medicinal chemistry letters (Bioorg Med Chem Lett) Vol. 23 Issue 5 Pg. 1498-501 (Mar 01 2013) ISSN: 1464-3405 [Electronic] England
• PMID: 23333208 (Publication Type: Journal Article)
• Copyright: Copyright © 2013 Elsevier Ltd. All rights reserved.

Chemical References

• Dopamine D2 Receptor Antagonists
• Receptors, Dopamine D1
• Receptors, Dopamine D2
• Tetrahydroisoquinolines

Topics

• Animals
• Dopamine D2 Receptor Antagonists
• Drug Design
• Male
• Mice
• Receptors, Dopamine D1 (agonists, metabolism)
• Receptors, Dopamine D2 (metabolism)
• Schizophrenia (drug therapy, pathology)
• Structure-Activity Relationship
• Tetrahydroisoquinolines (chemical synthesis, chemistry, pharmacology)