The present work will provide new insights into how drugs bind to and activate a family of receptors that are found throughout the central and peripheral nervous systems. These receptors are called Cys-loop receptors, and they are established therapeutic targets for Alzheimer's disease, schizophrenia, Parkinson's disease, pain, epilepsy, ADHD, autism, depression, addiction and more. Using powerful methodologies developed in previous years of the grant, the structures of the receptors can be modified in precise and subtle ways. In particular, the amino acids that are the building blocks of these protein receptors can be specifically replaced with designed, unnatural amino acids. This allows unprecedented control over the functionality present. How these modifications impact the effectiveness of drugs that target the receptor provides key insights into the mechanism of drug action. A key issue to be addressed will be receptor selectivity - how certain drugs are able to target only specific members of a collection of very closely related receptors. The knowledge generated from these studies will be very valuable to efforts to develop new pharmaceuticals to address the many neurological disorders associated with malfunctions of the Cys-loop receptors.

Public Health Relevance

Neurological disorders, including unipolar depressive disorders, bipolar affective disorder, and schizophrenia, present the greatest health hazard to adults in developed countries, according to the World Health Organization Global Burden of Disease assessment. The present work will provide new insights into how drugs bind to and activate a family of receptors found throughout the central and peripheral nervous systems. Malfunctions of these receptors are associated with the full spectrum of neurological disorders, and knowledge generated by this grant will be of great value to efforts to develop new pharmaceuticals to combat these dreaded diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS034407-19
Application #
8606660
Study Section
Synthetic and Biological Chemistry B Study Section (SBCB)
Program Officer
Stewart, Randall R
Project Start
1995-07-01
Project End
2017-02-28
Budget Start
2014-03-01
Budget End
2015-02-28
Support Year
19
Fiscal Year
2014
Total Cost
$753,948
Indirect Cost
$238,857
Name
California Institute of Technology
Department
Chemistry
Type
Schools of Engineering
DUNS #
009584210
City
Pasadena
State
CA
Country
United States
Zip Code
91125
Rienzo, Matthew; Rocchi, Angela R; Threatt, Stephanie D et al. (2016) Perturbation of Critical Prolines in Gloeobacter violaceus Ligand-gated Ion Channel (GLIC) Supports Conserved Gating Motions among Cys-loop Receptors. J Biol Chem 291:6272-80
Henderson, Brandon J; Lester, Henry A (2015) Inside-out neuropharmacology of nicotinic drugs. Neuropharmacology 96:178-93
Marotta, Christopher B; Lester, Henry A; Dougherty, Dennis A (2015) An Unaltered Orthosteric Site and a Network of Long-Range Allosteric Interactions for PNU-120596 in α7 Nicotinic Acetylcholine Receptors. Chem Biol 22:1063-73
Davis, Matthew R; Dougherty, Dennis A (2015) Cation-Ï€ interactions: computational analyses of the aromatic box motif and the fluorination strategy for experimental evaluation. Phys Chem Chem Phys 17:29262-70
Post, Michael R; Limapichat, Walrati; Lester, Henry A et al. (2015) Heterologous expression and nonsense suppression provide insights into agonist behavior at α6β2 nicotinic acetylcholine receptors. Neuropharmacology 97:376-82
Miles, Timothy F; Lester, Henry A; Dougherty, Dennis A (2015) Allosteric activation of the 5-HT3AB receptor by mCPBG. Neuropharmacology 91:103-8
Nichols, Weston A; Henderson, Brandon J; Yu, Caroline et al. (2014) Lynx1 shifts α4β2 nicotinic receptor subunit stoichiometry by affecting assembly in the endoplasmic reticulum. J Biol Chem 289:31423-32
Limapichat, Walrati; Dougherty, Dennis A; Lester, Henry A (2014) Subtype-specific mechanisms for functional interaction between α6β4* nicotinic acetylcholine receptors and P2X receptors. Mol Pharmacol 86:263-74
Marotta, Christopher B; Dilworth, Crystal N; Lester, Henry A et al. (2014) Probing the non-canonical interface for agonist interaction with an *5 containing nicotinic acetylcholine receptor. Neuropharmacology 77:342-9
Van Arnam, Ethan B; Dougherty, Dennis A (2014) Functional probes of drug-receptor interactions implicated by structural studies: Cys-loop receptors provide a fertile testing ground. J Med Chem 57:6289-300

Showing the most recent 10 out of 104 publications