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1. Discovery that the virus which causes 'HIV Dementia' (JC Virus) uses a GPCR to infect cells and that drugs
which block this receptor (5-HT2A serotonin receptor) block viral infection (Elphick et al). This discovery, highlighted in the
New York Times,
the BBC World News
and Science Express paves the way toward new treatments for
Progressive Multifocal Leukoencephalopathy. These studies were made possible by basic science studies performed by a former graduate student
Anushree Bhatnagar, PhD
(J. Biol. Chem., Vol. 279, Issue 33, 34614-34623
, J Biol Chem. 2003 Oct 31;278(44):43628-35, and supplemental video) wherein we used GFP-tagged GPCRs
to discover how these receptors were internalized.
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2. Discovery that the 'magic mint hallucinogen' (Salvinorin A) exerts its profound actions on human consciousness via activation of kappa opioid receptors (KORs; Roth et al,
Sheffler et al). This work has led to the suggestion that drugs which target KORs may be useful to treat many mental illnesses including schizophrenia and
Alzheimer's Disease
(Sheffler et al,
Munro et al).
In this vein, via the National Institute of Mental Health Psychoactive Drug Discovery Program (NIMH-PDSP),
we have a continuing large-scale effort to use receptoromics (the broad-based screening of the receptorome;
Armbruster et al)
to discover novel psychoactive and psychotherapeutic compounds (Fig 3). |
Figure 3: Physical Mining of the Receptorome Using Ligand-Binding Assays
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3. Discovered that drugs used in treating schizophrenia and bipolar disorder (atypical antipsychotic drugs) have an exceedingly
complex pharmacology and predicted that the next generation of medications will need to target multiple GPCRs to be clinically
effective
(Roth et al).
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4. Discovery that the now-banned appetite suppressant medication combination 'fen/phen' induces cardiovascular side-effects via activation
of the 5-HT2B serotonin receptor (Rothman et al,
Setola et al).
We have also discovered that several currently approved medications including drugs used to treat migraine headaches
(dihydroergotamine, methysergide) and Parkinson's Disease (pergolide, cabergoline) have the same liability
(Setola et al).
These studies have led to the suggestion that drugs which activate 5-HT2B receptors should not be administered to humans
(Rothman et al).
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5. Discovered a large number of GPCR-interacting proteins including Caveolin-1
(Bhatnagar et al) and PSD-95
(Xia et al)
and that these proteins profoundly modulate GPCR signaling. We currently have a large ongoing effort to discover novel GPCR interacting proteins.
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6. Discovery of the molecular mechanisms responsible for drug binding and activation of a prototypic GPCR
(Shapiro et al, Mol Pharm,
Shapiro et al, JBC, link to video showing receptor activation).
These studies continue and will, ultimately, lead to the 'in silico' design of novel therapeutic agents.
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