Dopamine D3/D2 Receptor Antagonist PF-4363467 Attenuates Opioid Drug-Seeking Behavior without Concomitant D2 Side Effects

• Published in: ACS chemical neuroscience Vol. 8; no. 1
• Main Authors: Wager, Travis T., Chappie, Thomas, Horton, David, Chandrasekaran, Ramalakshmi Y., Samas, Brian, Dunn-Sims, Elizabeth R., Hsu, Cathleen, Nawreen, Nawshaba, Vanase-Frawley, Michelle A., O’Connor, Rebecca E., Schmidt, Christopher J., Dlugolenski, Keith, Stratman, Nancy C., Majchrzak, Mark J., Kormos, Bethany L., Nguyen, David P., Sawant-Basak, Aarti, Mead, Andy N.
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society (ACS) 10.10.2016
• Subjects: 60 APPLIED LIFE SCIENCES; Antagonists; Central nervous system; cessation; CNS MPO; dopamine D2 antagonist; dopamine D3 antagonist; drug addiction; drug-seeking behavior; extrapyramidal symptoms; INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CHEMISTRY; locomotor; opioid; Pharmaceuticals; Receptors; reinstatement; Rodent models; Substance use dependence
• ISSN: 1948-7193; 1948-7193

Dopamine receptor antagonism is a compelling molecular target for the treatment of a range of psychiatric disorders, including substance use disorders. From our corporate compound file, we identified a structurally unique D3 receptor (D3R) antagonist scaffold, 1. Through a hybrid approach, we merged key pharmacophore elements from 1 and D3 agonist 2 to yield the novel D3R/D2R antagonist PF-4363467 (3). Compound 3 was designed to possess CNS drug-like properties as defined by its CNS MPO desirability score (≥4/6). In addition to good physicochemical properties, 3 exhibited low nanomolar affinity for the D3R (D3 Ki = 3.1 nM), good subtype selectivity over D2R (D2 Ki = 692 nM), and high selectivity for D3R versus other biogenic amine receptors. In vivo, 3 dose-dependently attenuated opioid self-administration and opioid drug-seeking behavior in a rat operant reinstatement model using animals trained to self-administer fentanyl. Further, traditional extrapyramidal symptoms (EPS), adverse side effects arising from D2R antagonism, were not observed despite high D2 receptor occupancy (RO) in rodents, suggesting that compound 3 has a unique in vivo profile. Collectively, our data support further investigation of dual D3R and D2R antagonists for the treatment of drug addiction.