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

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.

doi:10.1021/acschemneuro.6b00297

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

Journal Article · Mon Oct 10 00:00:00 EDT 2016 · ACS Chemical Neuroscience

DOI:https://doi.org/10.1021/acschemneuro.6b00297· OSTI ID:1440592

Wager, Travis T. ^[1]; Chappie, Thomas ^[1]; Horton, David ^[2]; Chandrasekaran, Ramalakshmi Y. ^[2]; Samas, Brian ^[2]; Dunn-Sims, Elizabeth R. ^[2]; Hsu, Cathleen ^[2]; Nawreen, Nawshaba ^[2]; Vanase-Frawley, Michelle A. ^[2]; O’Connor, Rebecca E. ^[2]; Schmidt, Christopher J. ^[1]; Dlugolenski, Keith ^[1]; Stratman, Nancy C. ^[1]; Majchrzak, Mark J. ^[3]; Kormos, Bethany L. ^[1]; Nguyen, David P. ^[1]; Sawant-Basak, Aarti ^[1]; Mead, Andy N. ^[2]

Pfizer Worldwide Research and Development, Cambridge, MA (United States)
Pfizer Worldwide Research and Development, Groton, CT (United States)
Pfizer Worldwide Research and Development, Chemistry and Biology, Eastern Point Road, Groton, Connecticut 06340, United States

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.

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Research Organization:: Argonne National Laboratory (ANL), Argonne, IL (United States). Advanced Photon Source (APS)

Sponsoring Organization:: USDOE Office of Science (SC)

OSTI ID:: 1440592

Journal Information:: ACS Chemical Neuroscience, Vol. 8, Issue 1; ISSN 1948-7193

Publisher:: American Chemical Society (ACS)Copyright Statement

Country of Publication:: United States

Language:: ENGLISH

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Cited by: 14 works

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60 APPLIED LIFE SCIENCES
37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CHEMISTRY
Rodent models
Antagonists
Central nervous system
Pharmaceuticals
Receptors
Substance use dependence
drug addiction
CNS MPO
dopamine D3 antagonist
dopamine D2 antagonist
opioid
cessation
drug-seeking behavior
reinstatement
extrapyramidal symptoms
locomotor