Design, synthesis, and evaluation of functionalized 5-(4-arylpiperazin-1-yl)-N-arylpentanamides as selective dopamine D3 receptor ligands

• Published in: Medicinal chemistry research Vol. 31; no. 1; pp. 132 - 145
• Main Authors: Blass, Benjamin E., Chen, Peng-Jen, Taylor, Michelle, Griffin, Suzy A., Gordon, John C., Luedtke, Robert R.
• Format: Journal Article
• Language: English
• Published: New York Springer US 2022; Springer Nature B.V
• Subjects: Biochemistry; Biomedical and Life Sciences; Biomedicine; Bioorganic Chemistry; Cocaine; Dopamine; Dopamine D2 receptors; Dopamine D3 receptors; Drug abuse; Drug development; Inorganic Chemistry; Lead compounds; Ligands; Medicinal Chemistry; Original Research; Pharmacology/Toxicology; Receptors; Selectivity; Therapeutic targets; Substance use disorder; Cocaine; Dopamine; D; dopamine receptor
• ISSN: 1054-2523; 1554-8120
• DOI: 10.1007/s00044-021-02825-3

Substance use disorder remains a major, unmet medical need. Cocaine is one of the most commonly abused recreational drugs and in 2018, there were over 5.5 million cocaine users. There are no approved therapies for the treatment of cocaine use disorder, but the D 3 dopamine receptor has been identified as a potential therapeutic target. Our initial lead compound ( 6 ) is a potent D 3 ligand with a high level of selectivity for D 3 over D 2 , but its solubility is low. We have identified a new series of functionalized 5-(4-arylpiperazin-1-yl)-N-arylpentanamides ( 7 ) that are potent D 3 binders that have moderate to high selectivity for D 3 over D 2 . Exemplary members of this series were also significantly more soluble than our initial lead compound ( 6 ).