Identification of new drug targets in

Schizophrenia
SMT. KISHORITAI BHOYAR COLLEGE OF PHARMACY, KAMPTEE.
Guide: Mr. Brijesh G. Taksande
Presented by: Nikitha S. Dambale
Contents
DRUG AND DRUG TARGETS,
METHODS OF TARGET IDENTIFICATION,
TYPES OF DRUG TARGET
SCHIZOPHRENIA AND ITS TYPES
CAUSES OF SCHIZOPHRENIA
TREATMENT OF SCHIZOPHRENIA
NEW DRUG TARGETS FOR SCHIZOPHRENIA

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Introduction
Drugs can be defined as chemical agents that uniquely
interacts with specific target molecules in the body,
thereby producing a biological effect. The word drug
derived from the French word drouge which means,
a dry herb

According to WHO : A drug is any
substance or product that is used
or intended to be used to modify
or explore physiological system
and pathological state for the
benefit of the recipient.


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Drug target:

A drug target is the
specific binding site of a
drug in vivo through
which the drug exerts its
action.

Biological targets are key
molecules involved in
metabolic or signaling
pathway.

Drugs work either by
stimulating or blocking
the activity of their target.


.

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A specific drug target might have the
following charachterstics:

1) The drug target is a biomolecule, normally a protein
that could exist in isolated or complex form.
2) The biomolecule have special sites that match other
molecules. These molecules could be endogenous
or extraneous substances such as chemical
molecules (drugs).
3) The physiological responses triggered by the
change in biomolecule structure play a major role in
complex regulation and have a therapeutic effect on
pathological conditions.
4) Drugs are generally much smaller than their targets.
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Macromolecular target
Drug
Unbound drug
Macromolecular target
Drug
Bound drug
Binding
site
Drug
Binding site
Binding
regions
Binding
groups
Intermolecular
bonds
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Drug discovery process
Drug Target
identification
Target
validation
Lead
identification
Lead
optimization
Preclinical
phase
Drug
discovery
2-5 years
Despite the enormous amount of public and private investment in
biomedical research, there has not been the expected increase in
new treatments for human disease, due to lack of knowledge of the
set of molecular targets that the modern pharmacopoeia acts on.

If we are to develop predictive methods to identify potential new drug
targets, it is essential that we establish with confidence the number,
characteristics and biological diversity of targets of approved drugs.
6-9 years
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Methods of target identification
Identification of novel drug targets that modulate or inhibit
these responses can be broadly divided into studies at
the physiological, network based approach or gene-
driven approach.

1. Physiological approach:
The physiological approach attempts to identify novel
targets through studies in whole organisms.
In the case of the physiology-driven approach, the
most important impact of molecular biology has been the
emergence of orphan receptors, transgenic and
knockout mouse models.
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Orphan receptors are receptors bind to unknown
chemicals. Scientists isolates cells and extracts their
RNA. They then made cDNA copies of the mRNAs and
determines the sequence of the nucleotide bases in
each cDNA molecule. By matching the DNA sequences
scientists were able to identify the corresponding genes,
and thus which genes are turned "on" in the nerve cells.

Knock outs can be produced by removing the gene or
inducing a mutation that disables its expression.

Transgenic animals are animals that are genetically
altered to have traits that mimic symptoms of specific
human pathologies. They provide genetic models of
various human diseases which are important in
understanding disease and developing new targets.
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2. The network-based approach
With the development of bioinformatics, a number of
computational techniques have been used to search for
novel drug targets, such as molecular docking.
Docking is the computational determination of binding
affinity between molecules (protein structure and ligand).
Most of target types can be stimulated or inhibited
depending of the ligand chosen.




The main goal is to predict the biological activity of a
given ligand.

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P L
L
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3. Gene-driven approach:
The final approach to the identification of potential
targets has been to compare the differential
expression of genes (genomics) in normal and
disease cells and tissues. Example : Human
Genome Project (HGP) is an international scientific
research project with a primary goal of determining
the sequence of chemical base pairs which make up
DNA and of identifying and mapping the
approximately 20,00025,000 genes of the human
genome from both a physical and functional
standpoint.

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Number of drug targets
Based on the mapping of the human genome in 2002, an estimated
8000 targets were identified.

Overingtons study (2006)
324 drug targets for all classes of approved therapeutic drugs
was proposed by Overington et al: 266 are HGD-proteins and
58 bacterial, viral, fungal or other organism targets.
27% binds to G-protein-coupled receptor
13% to nuclear receptors
7.9% to ligands-gated ion channels
5.5% to voltage-gated ion chanels
Imming et al study
218 listed targets: 66 human enzymes, 20 bacterial, viral and
fungal or parasital enzymes; 20 families of GPCR; 12 nuclear
receptors, 7 cytokine receptors and about 10 ion channels and 10
transport proteins of the plasma membrane

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Biochemical classes of drug targets:
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Case study : Schizophrenia
Schizophrenia occurs with regular frequency nearly every where
in the world.
About 1 in every 100 people are diagnosed with schizophrenia.
Schizophrenia is considered to be the most serious psychiatric
disorder. It usually starts during early adulthood.
Schizophrenia actually refers to a group of disorders. There is
not one essential symptom that must be present for diagnosis.
Instead, patients experience different combinations of the main
symptoms of schizophrenia
Schizophrenia is a serious mental illness characterized by a
disintegration of the process of thinking and of emotional
responsiveness.



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Schizophrenia
Complications:
Suicide 5-10% of deaths
Depression - occurs in 50% of cases, often
after an acute episode
Homelessness 30-35% of homeless
Crime: 4-fold increase in acts of violence
compared with the general population. These
patients are more frequently victims of both
violent and nonviolent crimes.
Substance abuse
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Positive and Negative Symptoms
Negative Positive
Alogia (reduced speech
output)
Hallucinations, most often
auditory
Affective flattening (blunted
emotional response)
Delusions of grandeur,
persecution, control, etc.
Catatonia (reduced
movement)
Bizarre behaviour
Avolition (lack of motivation) Disorder thought process
Social withdrawal Attentional impairment

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What causes schizophrenia?
Environment pregnancy and delivery complications
childhood and prenatal virus infection
urban birth and residence
psychosocial factors (dysfunctional family environment)
Changes in brain structure enlarged ventricles
reduced regional cerebral volumes
reduced activity in the temporal lobes
Heredity schizophrenia is genetically linked
more than one gene may predispose people to it
there is currently no reliable way to predict whether
a person will develop the disease.
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How is schizophrenia treated?
There is currently no cure for schizophrenia.
Treatment is aimed at reducing symptoms and preventing psychotic relapses.
Medication needs to be continue.
Two major types of antipsychotic medications (or neuroleptics):
CONVENTIONAL or TYPICAL ANTIPSYCHOTICS (haloperidol)
control the positive symptoms very effectively
side effects: extrapyramidal symptoms
(chronic: tardive dyskinesia, parkinsonism, akathisia;
acute: acute dystonia, neuroleptic malignant syndrome)
high affinity for D
2
dopamine receptors

NEWER or ATYPICAL ANTIPSYCHOTICS (clozapine, risperidone, olanzapine,
ziprasidone, quietapine, sertindole)
better at treating the negative symptoms
milder motor side effects; but others (weight gain, diabetes)

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The need for new drug targets
Current treatment modalities have certain limitations. While
the traditional antipsychotics have limitations like extra
pyramidal symptoms and tardive dyskinesia, newer anti
psychotics results in obesity, diabetes, and hyperlipidemia.
Disability of finding a solution to drugs severe side effects,
causing drug discontinuation or drug alterations and lower
drug compliance ratios of schizophrenia patients are the
reasons of new pharmacological seeking.
The research will pave the way for a new class of drugs to help
treat this devastating mental illness, which impacts 1 % of the
world's population, 30 % of whom do not respond to currently
available treatments.

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DRUG TARGETS

GLUTAMATERGIC TARGETS
It is the primary excitatory neurotransmitter in brain (60%
of the brain neurons). Glutamate mediates its CNS effects
via both ionotropic and metabotropic receptors.

There are 3 major classes of glutamatergic targets:
(i) NMDA receptors: Glycine transport inhibitors
(ii) AMPA
(iii)Metabotropic receptors
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(i) NMDA receptors
These receptors are involved in neuro development, neuroplasticity
and trophic brain functions,an ideal use of compounds in reversing
symptoms and neurocognitive changes early in schizophrenia.

Glycine transport inhibitors (GTIs) are used to increase
extracellular glycine levels, by preventing neuronal and glial uptake,
which brings about 17% reduction in negative symptoms.

(ii) AMPA(Alpha amino 3 hydroxy 5 methyl D aspartate) receptors
AMPA receptors act synergistically with NMDA receptors and are
needed to maintain overall integrity of glutamate synapses.
AMPAKines have been found to improve cognitive performance in
animal models. Farampator, a high potency ampakine has been
tested in healthy elderly volunteers and improved short term
memory.

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(iii)Metabotropic receptors
Ionotropic receptors are linked directly to ion channels,
metabotropic receptors are linked to second messenger
systems and affect neural metabolism, leading to the
alteration in glutamate release.

Metabotropic receptors are divided into 3 groups based
on functional activity and structure. One agent in
particular, LY354740, a group II agonist has been found to
reverse effects of NMDA antagonists in both rodents and
humans.
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NEUROSTEROID AND SIGMA RECEPTORS
It is well documented that sigma1 receptor ligands
increase the NMDA receptor response in the
hippocampus, suggesting a role in enhancing cognition.
Neurosteroids, such as dehydroepiandrosterone
(DHEA) and allopregnanolone, have been implicated in
neuroprotection and enhancement of NMDA receptor
neurotransmission, possibly through interaction with
sigma1 receptors, suggesting therapeutic potential for
enhancing cognition in schizophrenia.
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2-ADRENERGIC RECEPTORS
The central noradrenergic system projects from the locus
ceruleus to the prefrontal cortex where 2-adrenergic
receptors appear to play an important role in cognitive
functioning. Combined treatment of a typical
antipsychotic with the highly selective 2 adrenergic
receptor antagonist, idazoxan, has been reported to
produce a profile of antipsychotic activity similar to
clozapine. Thus, as 2-adrenergic receptor activity is
important in developing new drugs for schizophrenia that
can improve cognition.
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SUBEROYLANILIDE HYDROXAMIC ACID ( SAHA)
An enzyme called HDAC2 ( histone deacetylase 2) was highly
expressed in the brain of mice chronically treated with
antipsychotic drugs, resulting in lower expression of the
receptor called mGlu2, and a recurrence of psychotic
symptoms. A similar finding was observed in the postmortem
brains of schizophrenic patients.

The research team administered a chemical called
suberoylanilide hydroxamic acid (SAHA), which inhibits the
entire family of HDACs. They found that this treatment
prevented the detrimental effect of the anti psychotic called
clozapine on mGlu2 expression, and also improved the
therapeutic effects of atypical antipsychotics in mouse
models.

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