title: Dopamine D3/D2 Receptor Antagonist PF-4363467 Attenuates Opioid Drug-Seeking Behavior without Concomitant D2 Side Effects.
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.
authors.affiliation: Pfizer Worldwide Research and Development , Neuroscience Medicinal Chemistry and Neuroscience Research Unit, 610 Main Street, Cambridge, Massachusetts 02139, United States.
authors.forename: Travis T
authors.initials: TT
authors.lastname: Wager
authors.affiliation: Pfizer Worldwide Research and Development , Neuroscience Medicinal Chemistry and Neuroscience Research Unit, 610 Main Street, Cambridge, Massachusetts 02139, United States.
authors.forename: Thomas
authors.initials: T
authors.lastname: Chappie
authors.affiliation: Pfizer Worldwide Research and Development , Chemistry and Biology, Eastern Point Road, Groton, Connecticut 06340, United States.
authors.forename: David
authors.initials: D
authors.lastname: Horton
authors.affiliation: Pfizer Worldwide Research and Development , Chemistry and Biology, Eastern Point Road, Groton, Connecticut 06340, United States.
authors.forename: Ramalakshmi Y
authors.initials: RY
authors.lastname: Chandrasekaran
authors.affiliation: Pfizer Worldwide Research and Development , Chemistry and Biology, Eastern Point Road, Groton, Connecticut 06340, United States.
authors.forename: Brian
authors.initials: B
authors.lastname: Samas
authors.affiliation: Pfizer Worldwide Research and Development , Chemistry and Biology, Eastern Point Road, Groton, Connecticut 06340, United States.
authors.forename: Elizabeth R
authors.initials: ER
authors.lastname: Dunn-Sims
authors.affiliation: Pfizer Worldwide Research and Development , Chemistry and Biology, Eastern Point Road, Groton, Connecticut 06340, United States.
authors.forename: Cathleen
authors.initials: C
authors.lastname: Hsu
authors.affiliation: Pfizer Worldwide Research and Development , Chemistry and Biology, Eastern Point Road, Groton, Connecticut 06340, United States.
authors.forename: Nawshaba
authors.initials: N
authors.lastname: Nawreen
authors.affiliation: Pfizer Worldwide Research and Development , Chemistry and Biology, Eastern Point Road, Groton, Connecticut 06340, United States.
authors.forename: Michelle A
authors.initials: MA
authors.lastname: Vanase-Frawley
authors.affiliation: Pfizer Worldwide Research and Development , Chemistry and Biology, Eastern Point Road, Groton, Connecticut 06340, United States.
authors.forename: Rebecca E
authors.initials: RE
authors.lastname: O'Connor
authors.affiliation: Pfizer Worldwide Research and Development , Neuroscience Medicinal Chemistry and Neuroscience Research Unit, 610 Main Street, Cambridge, Massachusetts 02139, United States.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Schmidt
authors.affiliation: Pfizer Worldwide Research and Development , Neuroscience Medicinal Chemistry and Neuroscience Research Unit, 610 Main Street, Cambridge, Massachusetts 02139, United States.
authors.forename: Keith
authors.initials: K
authors.lastname: Dlugolenski
authors.affiliation: Pfizer Worldwide Research and Development , Neuroscience Medicinal Chemistry and Neuroscience Research Unit, 610 Main Street, Cambridge, Massachusetts 02139, United States.
authors.forename: Nancy C
authors.initials: NC
authors.lastname: Stratman
authors.affiliation: Pfizer Worldwide Research and Development , Chemistry and Biology, Eastern Point Road, Groton, Connecticut 06340, United States.
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Majchrzak
authors.affiliation: Pfizer Worldwide Research and Development , Neuroscience Medicinal Chemistry and Neuroscience Research Unit, 610 Main Street, Cambridge, Massachusetts 02139, United States.
authors.forename: Bethany L
authors.initials: BL
authors.lastname: Kormos
authors.affiliation: Pfizer Worldwide Research and Development , Pharmacokinetics, Dynamics, and Metabolism, 610 Main Street, Cambridge, Massachusetts 02139, United States.
authors.forename: David P
authors.initials: DP
authors.lastname: Nguyen
authors.affiliation: Pfizer Worldwide Research and Development , Pharmacokinetics, Dynamics, and Metabolism, 610 Main Street, Cambridge, Massachusetts 02139, United States.
authors.forename: Aarti
authors.initials: A
authors.lastname: Sawant-Basak
authors.affiliation: Pfizer Worldwide Research and Development , Chemistry and Biology, Eastern Point Road, Groton, Connecticut 06340, United States.
authors.forename: Andy N
authors.initials: AN
authors.lastname: Mead
mesh_terms: D000701:Analgesics, Opioid / Q000009:adverse effects*; D000814:Aniline Compounds / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D002461:Cell Line, Transformed; D003216:Conditioning, Operant / Q000187:drug effects; D015259:Dopamine Agents / Q000494:pharmacology; D065127:Dopamine D2 Receptor Antagonists / Q000737:chemistry* / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D058999:Drug-Seeking Behavior / Q000187:drug effects*; D005283:Fentanyl / Q000009:adverse effects; D006801:Humans; D008297:Male; D009447:Neuroblastoma / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D017448:Receptors, Dopamine D2 / Q000378:metabolism; D050637:Receptors, Dopamine D3 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D012646:Self Administration; D013449:Sulfonamides / Q000737:chemistry / Q000494:pharmacology; D000096926:Benzenesulfonamides
chemical_list: D000701:Analgesics, Opioid; D000814:Aniline Compounds; D015259:Dopamine Agents; D065127:Dopamine D2 Receptor Antagonists; D005283:Fentanyl; D017448:Receptors, Dopamine D2; D050637:Receptors, Dopamine D3; D013449:Sulfonamides; C000624284:PF-4363467; D000096926:Benzenesulfonamides
keywords: CNS MPO; Substance use dependence; cessation; dopamine D2 antagonist; dopamine D3 antagonist; drug addiction; drug-seeking behavior; extrapyramidal symptoms; locomotor; opioid; reinstatement