Transcript mgluR`s in schizo.

Positive Allosteric Modulators of
Metabotropic Glutamate Receptors in
Schizophrenia
PHM142 Fall 2014
Coordinator: Dr. Jeffrey Henderson
Instructor: Dr. David Hampson
Amanda Debreceni
Samier Kamar
Alex Mok
Ran Shu
Tuesday October 28th 2014
Learning Objectives
• Define schizophrenia
• Define PAM (Positive Allosteric Modulators)
• Metabotropic Glutamate Receptors
(mGluR2/mGluR3)
• Pre-Clinical trials concerning PAMs
• Current and future treatments for
schizophrenia
• Summary slide
What is Schizophrenia?
• Complex disease with:
– Positive Symptoms
Cognitive
Impairments
– Negative Symptoms
• Current Treatments have side effects:
– Less effective in reducing the negative symptoms
Positive Allosteric Activation
Types of Glutamate Receptors
Metabotropic Glutamate Receptor
Schizophrenic
PatientsPatients
Normal
Location of mGluR2 and mGluR3
• Mostly in the forebrain
– In presynaptic neurons throughout the prefrontal
cortex
Location of mGluR2 and mGluR3
• Mostly in the forebrain
– Highest mRNA levels of mGluR2 are found in the
prefrontal cortex
Compounds in the Literature Currently
• Agonists of group II mGluR (mGluR2 and
mGluR3)
– LY404039 (Phase II and III)
• Positive Allosteric Modulators
– More specific (target mGluR2 only)
– LY487379 (LY48) and others of first series
– Biphenyl-indanone A (BINA) and second series
BINA Experiments in Mice
• Effectiveness in Different Mouse Models (2
Models)
– Amphetamine-Induced Hyperlocomotor Activity
– PCP-Induced Hyperlocomotor Activity
• Compared to LY487379
– Different Results
– BINA has longer half-life
Discussion of Experiment
• Off target effects?
• Agonist Receptor Trafficking
• Evidence that mGluR2 PAMS can be an
alternative to Agonists
Treatments for Schizophrenia
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Drugs Targeting Dopamine Imbalance
Psychosocial Therapy
Electroconvulsive Therapy
Drugs Targeting Glutamate?
Summary Slide
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Schizophrenia is a complex disease characterized by positive and negative symptoms (positive:
hallucinations, negative: social withdrawal)
It is characterized by cognitive impairments and increased glutamate in the prefrontal cortex limbic
system
Glutamate exacerbates the symptoms of schizophrenia patients
PAM- Binds to an allosteric site (not active site), enhances the activity of the agonist leading to
downstream effects
Glutamate Receptors are Metabotropic Receptors
In schizophrenic patients, there is reduced Gαi activity, leading to increased adenylyl cyclase activity
+ calcium ion increase = increased glutamate
In normal patients, Gαi inhibits the effect of adenylyl cyclase activity and calcium activity
BINA blocks the PCP-Induced Hyperlocomotor Activity whereas LY487379 blocked the
Amphetamine-Induced Hyperlocomotor Activity
The differences may be due to off target effects, which means that different compounds can
activate different pathways from the same receptor.
Treatments for Schizophrenia
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Drugs Targeting Dopamine Imbalance
Psychosocial Therapy
Electroconvulsive Therapy
Drugs Targeting Glutamate Imbalance in the future
References
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Eli Lilly and Company - Lilly Stops Phase III Development of Pomaglumetad Methionil For the Treatment of
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Conn, J. et al., 2009. Activation of metabotropic glutamate receptors as a novel approach for the treatment of
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Frooninckx, L. et al., 2012. Neuropeptide GPCRs in C. elegans. Front Endocrinology, 3: 167.
Galici R, Jones CK, Hemstapat K, Nong Y, Echemendia NG, Williams LC, et al. Biphenyl-indanone A, a positive
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