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 in | ACS chemical neuroscience Vol. 8; no. 1; pp. 165 - 177 |
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Main Authors | , , , , , , , , , , , , , , , , , |
Format | Journal Article |
Language | English |
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American Chemical Society
18.01.2017
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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 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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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. 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. 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 = 3.1 nM), good subtype selectivity over D2R (D2 K = 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 Wager, Travis T O’Connor, Rebecca E Mead, Andy N Dlugolenski, Keith Vanase-Frawley, Michelle A Nawreen, Nawshaba Hsu, Cathleen Majchrzak, Mark J Nguyen, David P Dunn-Sims, Elizabeth R Kormos, Bethany L Chandrasekaran, Ramalakshmi Y Schmidt, Christopher J Horton, David Samas, Brian Stratman, Nancy C Sawant-Basak, Aarti |
AuthorAffiliation | Chemistry and Biology Pfizer Worldwide Research and Development Neuroscience Medicinal Chemistry and Neuroscience Research Unit Pharmacokinetics, Dynamics, and Metabolism |
AuthorAffiliation_xml | – name: Pharmacokinetics, Dynamics, and Metabolism – name: Chemistry and Biology – name: Pfizer Worldwide Research and Development – name: Neuroscience Medicinal Chemistry and Neuroscience Research Unit |
Author_xml | – sequence: 1 givenname: Travis T surname: Wager fullname: Wager, Travis T email: travis.t.wager@pfizer.com – sequence: 2 givenname: Thomas surname: Chappie fullname: Chappie, Thomas – sequence: 3 givenname: David surname: Horton fullname: Horton, David – sequence: 4 givenname: Ramalakshmi Y surname: Chandrasekaran fullname: Chandrasekaran, Ramalakshmi Y – sequence: 5 givenname: Brian surname: Samas fullname: Samas, Brian – sequence: 6 givenname: Elizabeth R surname: Dunn-Sims fullname: Dunn-Sims, Elizabeth R – sequence: 7 givenname: Cathleen surname: Hsu fullname: Hsu, Cathleen – sequence: 8 givenname: Nawshaba surname: Nawreen fullname: Nawreen, Nawshaba – sequence: 9 givenname: Michelle A surname: Vanase-Frawley fullname: Vanase-Frawley, Michelle A – sequence: 10 givenname: Rebecca E surname: O’Connor fullname: O’Connor, Rebecca E – sequence: 11 givenname: Christopher J surname: Schmidt fullname: Schmidt, Christopher J – sequence: 12 givenname: Keith surname: Dlugolenski fullname: Dlugolenski, Keith – sequence: 13 givenname: Nancy C surname: Stratman fullname: Stratman, Nancy C – sequence: 14 givenname: Mark J surname: Majchrzak fullname: Majchrzak, Mark J – sequence: 15 givenname: Bethany L surname: Kormos fullname: Kormos, Bethany L – sequence: 16 givenname: David P surname: Nguyen fullname: Nguyen, David P – sequence: 17 givenname: Aarti surname: Sawant-Basak fullname: Sawant-Basak, Aarti – sequence: 18 givenname: Andy N surname: Mead fullname: Mead, Andy N |
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Keywords | drug-seeking behavior reinstatement Substance use dependence dopamine D3 antagonist opioid cessation drug addiction CNS MPO dopamine D2 antagonist extrapyramidal symptoms locomotor |
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SubjectTerms | 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 |
Title | Dopamine D3/D2 Receptor Antagonist PF-4363467 Attenuates Opioid Drug-Seeking Behavior without Concomitant D2 Side Effects |
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