This K02 Award will fund the salary support for all of Dr. Roth's research related activities. Three major goals are proposed for this funding cycle including: (1) Characterization of the structure and function of 5-HT2-family serotonin receptors; (2) Discovering the cellular and molecular mechanisms responsible for the regulation of 5-HT2A receptors and (3) Administering the National Institute of Mental Health Psychoactive Drug Screening Program. Characterizing the structure and function of 5-HT2A receptors is of great importance for mental health-related research because a number of psychoactive compounds including atypical antipsychotic drugs, antidepressants and some anxiolytic medications exert their actions via interacting with 5-HT2A receptors. Understanding how such drugs interact with 5-HT2-family receptors at the atomic level may lead to novel insights into drug design and development. Discovering how the 5-HT2A receptor is regulated is important for understanding the pharmacological mechanisms by which drugs may regulate neurotransmitter receptor levels. 5-HT2A receptors are regulated in a paradoxical manner by antagonists and insights into the cellular and molecular mechanisms by which these alterations occur could be of importance for understanding 6-protein receptor coupled regulation. Finally, the NIMH Psychoactive Drug Screening Program is responsible for characterizing the pharmacology of novel psychoactive compounds, some of which may represent new therapeutic agents. A full molecular pharmacologic characterization of these compounds is essential prior to their use in humans.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Scientist Development Award - Research (K02)
Project #
5K02MH001366-09
Application #
6801878
Study Section
Special Emphasis Panel (ZRG1-SSS-Q (01))
Program Officer
Brady, Linda S
Project Start
1996-07-01
Project End
2006-08-31
Budget Start
2004-09-01
Budget End
2005-08-31
Support Year
9
Fiscal Year
2004
Total Cost
$118,584
Indirect Cost
Name
Case Western Reserve University
Department
Biochemistry
Type
Schools of Medicine
DUNS #
077758407
City
Cleveland
State
OH
Country
United States
Zip Code
44106
Dewkar, Gajanan K; Peddi, Srinivas; Mosier, Philip D et al. (2008) Methoxy-substituted 9-aminomethyl-9,10-dihydroanthracene (AMDA) derivatives exhibit differential binding affinities at the 5-HT(2A) receptor. Bioorg Med Chem Lett 18:5268-71
Armbruster, Blaine N; Li, Xiang; Pausch, Mark H et al. (2007) Evolving the lock to fit the key to create a family of G protein-coupled receptors potently activated by an inert ligand. Proc Natl Acad Sci U S A 104:5163-8
Davies, M A; Setola, V; Strachan, R T et al. (2006) Pharmacologic analysis of non-synonymous coding h5-HT2A SNPs reveals alterations in atypical antipsychotic and agonist efficacies. Pharmacogenomics J 6:42-51
Chemel, Benjamin R; Roth, Bryan L; Armbruster, Blaine et al. (2006) WAY-100635 is a potent dopamine D4 receptor agonist. Psychopharmacology (Berl) 188:244-51
Roth, Bryan L; Kroeze, Wesley K (2006) Screening the receptorome yields validated molecular targets for drug discovery. Curr Pharm Des 12:1785-95
Sheffler, Douglas J; Kroeze, Wesley K; Garcia, Bonnie G et al. (2006) p90 ribosomal S6 kinase 2 exerts a tonic brake on G protein-coupled receptor signaling. Proc Natl Acad Sci U S A 103:4717-22
Vercouillie, Johnny; Mavel, Sylvie; Galineau, Laurent et al. (2006) Synthesis and in vitro evaluation of novel derivatives of diphenylsulfide as serotonin transporter ligands. Bioorg Med Chem Lett 16:1297-300
Strachan, Ryan T; Ferrara, Gina; Roth, Bryan L (2006) Screening the receptorome: an efficient approach for drug discovery and target validation. Drug Discov Today 11:708-16
Kushwaha, Neena; Harwood, Shannon C; Wilson, Ariel M et al. (2006) Molecular determinants in the second intracellular loop of the 5-hydroxytryptamine-1A receptor for G-protein coupling. Mol Pharmacol 69:1518-26
Pehek, Elizabeth A; Nocjar, Christine; Roth, Bryan L et al. (2006) Evidence for the preferential involvement of 5-HT2A serotonin receptors in stress- and drug-induced dopamine release in the rat medial prefrontal cortex. Neuropsychopharmacology 31:265-77

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