Selective D4R Ligands Reveal Structure-Activity Relationships that Engender Agonist Efficacy

Presented at: Neuroscience 2020
C.E. Credits: P.A.C.E. CE Florida CE
  • Assistant Professor, High Point University
      Dr. Comfort A. Boateng received her PhD in Pharmaceutical Sciences specializing in medicinal chemistry from Florida A & M University, Tallahassee, FL, in 2010. She received national awards such as the Graduate Assistance in Areas of National Need (GAANN) fellowship (2005-2008), National Institute of Health (NIH)/Intramural NIAID Research Opportunity (INRO) Award (2008), and Merck & Company - American Foundation for Pharmaceutical Education Minority Pre-Doctoral Fellowship Award in Pharmaceutical Sciences (2008-2010) and research fellowship in laboratory of Clinical Infectious Diseases at NIH/NIAID in 2008. Followed by postdoctoral studies in the Medicinal Chemistry Section of the Molecular Targets and Medications Discovery Branch, Intramural Research Program of the National Institute on Drug Abuse (NIDA-IRP) where she was the recipient of the NIDA Scientific Director's Fellowship for Diversity in Research (2011-2014) and NIH Fellows Award for Research Excellence (2015). Dr. Boateng joined the High Point University (HPU) Fred Wilson School of Pharmacy as an Assistant Professor in the Basic Pharmaceutical Sciences Department since 2015. Since joining HPU, she has received national awards such as Maharaj Ticku New Investigator Award by Behavior, Biology, and Chemistry: Translational Research in Addiction, NIH/NIDA Diversity Scholars Network program, Organic/Bioorganic-Mentoring Workshop Fellowship by NIH/NIGM. She is serving on numerous local and national committees such as NIH Early Career Reviewer, American Chemical Society-Committee on Minority Affairs (CMA), American Association for Colleges of Pharmacy (AACP)-Medicinal Chemistry Programming Section and AACP HPU faculty delegate including HPU-Intramural Research Award, 2020 AACP-NIA, AFPE, Project-SEED, NIH/NIDA Diversity supplement grants. At the School of Pharmacy, her duties include lecturing on medicinal chemistry principles, neuroscience, anti-infectives, cancer, natural products, and also serving on HPU academic committees and supervising research. She has published in peer-reviewed journals in areas such as CNS disorders and opportunistic pathogens. The focus of Dr. Boateng's current research interest is design, synthesis and pharmacological evaluation of selective ligands for the dopaminergic receptor systems, as molecular tools and leads toward potential treatment medications for psychostimulant abuse and other neuropsychiatric disorders.


    The dopamine D4 receptor (D4R) is enriched in the prefrontal cortex where it plays important roles in cognition, attention, decision making and executive function. Novel D4R-selective ligands have promise in medication development for neuropsychiatric conditions, including Alzheimer’s disease and substance use disorders (SUD). To identify new D4R-selective ligands, and to understand the molecular determinants of agonist efficacy at D4R, we report a series of eighteen novel ligands based on the classical D4R agonist A-412997 (2-(4-(pyridin-2-yl)piperidin-1-yl)-N-(m-tolyl)acetamide). Compounds were profiled using radioligand binding displacement assays, β-arrestin recruitment assays, cAMP inhibition assays, and molecular dynamic computational modeling. We identified several novel D4R-selective (Ki ≤ 4.3 nM and >100-fold vs. other D2-like receptors) compounds with diverse partial agonist and antagonist profiles, falling into three structural groups. These compounds highlight receptor-ligand interactions that control efficacy at D2-like receptors and may provide insights to targeted drug discovery leading to a better understanding of the role of D4Rs in neuropsychiatric disorders such as SUD.

    Learning Objectives:

    1.  Identify various challenges in designing medication in treating Substance Use Disorders

    2.  Understanding the role of dopamine receptors in developing therapies for the treatment of  Substance Use Disorders

    3. Understanding of receptor-ligand interactions that control efficacy.

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