Discovery, characterization and biological evaluation of a novel (R)-4,4-difluoropiperidine scaffold as dopamine receptor 4 (D4R) antagonists.
Herein, we report the synthesis and structure-activity relationship of a novel series of (R)-4,4-difluoropiperidine core scaffold as dopamine receptor 4 (D4) antagonists. A series of compounds from this scaffold are highly potent against the D4receptor and selective against the other dopamine receptors. In addition, we were able to confirm the active isomer as the (R)-enantiomer via an X-ray crystal structure.
Department of Chemistry, Vanderbilt University, Nashville, TN 37232, United States.
Daniel E
DE
Jeffries
Department of Chemistry, Vanderbilt University, Nashville, TN 37232, United States.
Jonathan O
JO
Witt
Department of Chemistry, Vanderbilt University, Nashville, TN 37232, United States.
Andrea L
AL
McCollum
Department of Pharmacology, Vanderbilt University, Nashville, TN 37232, United States; Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University, Nashville, TN 37232, United States.
Kayla J
KJ
Temple
Department of Pharmacology, Vanderbilt University, Nashville, TN 37232, United States.
Miguel A
MA
Hurtado
Department of Biochemistry, Vanderbilt University, Nashville, TN 37232, United States.
Joel M
JM
Harp
Department of Pharmacology, Vanderbilt University, Nashville, TN 37232, United States; Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University, Nashville, TN 37232, United States.
Anna L
AL
Blobaum
Department of Chemistry, Vanderbilt University, Nashville, TN 37232, United States; Department of Pharmacology, Vanderbilt University, Nashville, TN 37232, United States; Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University, Nashville, TN 37232, United States.
Craig W
CW
Lindsley
Department of Chemistry, Vanderbilt University, Nashville, TN 37232, United States; Department of Pharmacology, Vanderbilt University, Nashville, TN 37232, United States; Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University, Nashville, TN 37232, United States; Department of Pharmaceutical Sciences, College of Pharmacy, University of Nebraska Medical Center, Omaha, NE 58198, United States. Electronic address: corey.hopkins@unmc.edu.
Corey R
CR
Hopkins
D000818:Animals; D014150:Antipsychotic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D018360:Crystallography, X-Ray; D018492:Dopamine Antagonists / Q000737:chemistry* / Q000494:pharmacology*; D055808:Drug Discovery; D054879:Halogenation; D006801:Humans; D007536:Isomerism; D008958:Models, Molecular; D010880:Piperidines / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D050638:Receptors, Dopamine D4 / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism
D014150:Antipsychotic Agents; D018492:Dopamine Antagonists; D010880:Piperidines; D050638:Receptors, Dopamine D4
Addiction; Difluoropiperidine; Dopamine 4 receptor; PD-LIDs; Selectivity