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

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...

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Published inACS 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
LanguageEnglish
Published United States American Chemical Society (ACS) 10.10.2016
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Abstract 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.
AbstractList 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.
Author Chappie, Thomas
Dlugolenski, Keith
Chandrasekaran, Ramalakshmi Y.
Nawreen, Nawshaba
Vanase-Frawley, Michelle A.
Mead, Andy N.
Nguyen, David P.
Majchrzak, Mark J.
Schmidt, Christopher J.
Hsu, Cathleen
Kormos, Bethany L.
Wager, Travis T.
Dunn-Sims, Elizabeth R.
Stratman, Nancy C.
O’Connor, Rebecca E.
Horton, David
Samas, Brian
Sawant-Basak, Aarti
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  organization: Pfizer Worldwide Research and Development, Groton, CT (United States)
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Snippet Dopamine receptor antagonism is a compelling molecular target for the treatment of a range of psychiatric disorders, including substance use disorders. From...
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SubjectTerms 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
Title Dopamine D3/D2 Receptor Antagonist PF-4363467 Attenuates Opioid Drug-Seeking Behavior without Concomitant D2 Side Effects
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