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; pp. 165 - 177
• 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 18.01.2017
• Subjects: Analgesics, Opioid - adverse effects; Aniline Compounds - chemistry; Aniline Compounds - pharmacology; Animals; Cell Line, Transformed; Conditioning, Operant - drug effects; Dopamine Agents - pharmacology; Dopamine D2 Receptor Antagonists - chemistry; Dopamine D2 Receptor Antagonists - pharmacology; Dose-Response Relationship, Drug; Drug-Seeking Behavior - drug effects; Fentanyl - adverse effects; Humans; Male; Neuroblastoma - pathology; Rats; Rats, Sprague-Dawley; Receptors, Dopamine D2 - metabolism; Receptors, Dopamine D3 - antagonists & inhibitors; Receptors, Dopamine D3 - metabolism; Self Administration; Sulfonamides - chemistry; Sulfonamides - pharmacology; drug-seeking behavior; reinstatement; Substance use dependence; dopamine D3 antagonist; opioid; cessation; drug addiction; CNS MPO; dopamine D2 antagonist; extrapyramidal symptoms; locomotor
• ISSN: 1948-7193; 1948-7193
• DOI: 10.1021/acschemneuro.6b00297

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 K i = 3.1 nM), good subtype selectivity over D2R (D2 K i = 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.