Medications Discovery Research Branch
Medicinal Chemistry Section
Mission Statement
The mission of the NIDA-IRP Medicinal Chemistry Section is to design and synthesize novel ligands to study the role of central dopaminergic (D2-family) and metabotropic glutamatergic (mGluR5) receptors and monoamine transporters in cocaine abuse. Highly selective compounds are designed and synthesized for characterization of these molecular targets through the development of structure-activity relationships and molecular modeling. In addition, molecular tools are synthesized such as fluorescent, irreversible and radiolabeled ligands, for receptor topological mapping studies and the elucidation of pharmacological function.
Program Areas
The design, synthesis and pharmacological evaluation of novel dopamine uptake inhibitors, dopamine receptor subtype-selective ligands (D2 and D3) and mGluR5 allosteric modulators are being targeted for elucidating neurochemical mechanisms underlying cocaine abuse and addiction. Molecular modeling using 3D QSAR methodologies for drug design and binding domain characterization are currently being employed for the discovery of novel tools for both molecular-level and in vivo investigation.
Name: Amy Hauck Newman, Ph.D.
Title: Senior Investigator and Chief, Medicinal Chemistry Section
Telephone Number: (410) 550-1455 X114
Synopsis of Research
The design and synthesis of novel compounds provide molecular tools with which to study the roles of the dopamine transporter, the dopamine D2 family of receptors, and the metabotropic glutamate receptors (mGluR5) in the reinforcing effects of and ultimately the addiction to cocaine. The compounds are designed to bind with high affinity and selectivity to these protein targets and are used to relate molecular substrates to cocaine-like behavior, using both in vitro and in vivo models of cocaine abuse. Highly potent and selective dopamine uptake inhibitors have been discovered, based on benztropine that are not cocaine-like in vivo and can attenuate many cocaine-induced behaviors. Structure-activity relationships and molecular models support distinctive binding modes for these classes of dopamine uptake inhibitors, as compared to cocaine. Irreversible ligands, based on benztropine and the 3-phenyltropane class of dopamine uptake inhibitors, in combination with immunological peptide mapping and site-directed mutagenesis, are providing molecular identification of transmembrane binding domains on the dopamine transporter. In addition, the roles of all three monoamine transporters, sigma receptors, and dopamine D2-like receptors in cocaine’s actions are also being investigated. As our understanding of the molecular mechanisms underlying cocaine abuse improves, chemical structure modification, using rational drug design, can appropriately manipulate both pharmacokinetics and pharmacodynamics of these agents and may result in effective cocaine abuse therapeutics.
|
|
|
Medications Discovery Research Branch
|
|
