David R. Sibley, Ph.D.
Molecular Neuropharmacology Section
Building 35, Room 3A201
35 Convent Drive
Bethesda, MD 20892-3723
The long-term goal of the Molecular Neuropharmacology Section is the characterization of neurotransmitter receptor-mediated information transduction, and its regulation, across neuronal membranes. The primary model systems under investigation are those neurotransmitter receptors that are linked to their signal transduction pathways via guanine nucleotide binding regulatory (G) proteins with specific emphasis on dopamine receptor subtypes. Specific G proteins have been shown to link these receptors to the activation and inhibition of various nucleotide cyclases, phospholipases, and several ion channels. In order to characterize these receptors at the biochemical and molecular levels and study their regulation, there are several ongoing interrelated lines of research. Such projects include investigating receptor structure/function/pharmacology relationships, receptor-effector coupling mechanisms, G protein and beta-arrestin interactions, and molecular mechanisms of receptor desensitization and intracellular trafficking. We are also interested in using high throughput screening approaches to develop novel ligands for modulating dopamine receptor expression and signaling. Novel modulator compounds have been identified for D1, D2, and D3 receptor subtypes and are in various stages of development into drug candidates. These compounds may prove useful for novel pharmacological therapies for treating numerous neurological and psychiatric disorders associated with aberrant dopaminergic signaling.
Sanchez-Soto M, Verma RK, Willette BKA, Gonye EC, Moore AM, Moritz AE, Boateng CA, Yano H, Free RB, Shi L, Sibley DR. A structural basis for how ligand binding site changes can allosterically regulate GPCR signaling and engender functional selectivity. Sci Signal. 2020;13(617).
Moritz AE, Free RB, Weiner WS, Akano EO, Gandhi D, Abramyan A, Keck TM, Ferrer M, Hu X, Southall N, Steiner J, Aubé J, Shi L, Frankowski KJ, Sibley DR. Discovery, Optimization, and Characterization of ML417: A Novel and Highly Selective D<sub>3</sub> Dopamine Receptor Agonist. J Med Chem. 2020;63(10):5526-5567.
Luderman KD, Conroy JL, Free RB, Southall N, Ferrer M, Sanchez-Soto M, Moritz AE, Willette BKA, Fyfe TJ, Jain P, Titus S, Hazelwood LA, Aubé J, Lane JR, Frankowski KJ, Sibley DR. Identification of Positive Allosteric Modulators of the D<sub>1</sub> Dopamine Receptor That Act at Diverse Binding Sites. Mol Pharmacol. 2018;94(4):1197-1209.
Chun LS, Vekariya RH, Free RB, Li Y, Lin DT, Su P, Liu F, Namkung Y, Laporte SA, Moritz AE, Aubé J, Frankowski KJ, Sibley DR. Structure-Activity Investigation of a G Protein-Biased Agonist Reveals Molecular Determinants for Biased Signaling of the D<sub>2</sub> Dopamine Receptor. Front Synaptic Neurosci. 2018;10:2.
Kumar V, Moritz AE, Keck TM, Bonifazi A, Ellenberger MP, Sibley CD, Free RB, Shi L, Lane JR, Sibley DR, Newman AH. Synthesis and Pharmacological Characterization of Novel trans-Cyclopropylmethyl-Linked Bivalent Ligands That Exhibit Selectivity and Allosteric Pharmacology at the Dopamine D<sub>3</sub> Receptor (D<sub>3</sub>R). J Med Chem. 2017;60(4):1478-1494.
Related Scientific Focus Areas
Molecular Biology and Biochemistry
This page was last updated on September 1st, 2020