Schizophrenia (3)

8/11/2019 Schizophrenia (3)

1/26

Identification of new drug targets in

Schizophrenia

SMT. KISHORITAI BHOYAR COLLEGE OF PHARMACY, KAMPTEE.

Guide: Mr. Brijesh G. Taksande

Presented by: Nikitha S. Dambale


2/26

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

2


3/26

Introduction

Drugscan 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.

3


4/26

Drug target:

A drug target isthespecific 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. 4


5/26

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 endogenousor 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.

5


6/26

Macromolecular target

Drug

Unbound drug

Macromolecular target

Drug

Bound drug

Binding

site

Drug

Binding site

Binding

regions

Binding

groups

Intermolecular

bonds

6


7/26

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 theset 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

7


8/26

Methods of target identification

Identification of novel drug targets that modulate or inhibitthese responses can be broadly divided into studies at

the physiological, networkbased approachor gene-

driven approach.

1. Physio log ical approach :

The physiological approach attempts to identify novel

targets through studies in whole organisms.

In the case of the physiology-driven approach, themost important impact of molecular biology has been the

emergence of orphan receptors, transgenicand

knockout mouse models.

8


9/26

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 geneticallyaltered 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.9


10/26

2. The network-based approach

With the development of bioinformatics, a number of

computational techniques have been used to search fornovel drug targets, such as molecular docking.

Dockingis the computational determination of bindingaffinity between molecules (protein structure and ligand).

Most of target types can be stimulated or inhibiteddepending of the ligand chosen.

The main goal is to predict the biological activity of a

given ligand.

10

PL

L

P


11/26

3. Gene-d riven app roach :

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 determiningthe 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 functionalstandpoint.

11


12/26

Number of drug targetsBased 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 nuclearreceptors, 7 cytokine receptors and about 10 ion channels and 10transport proteins of the plasma membrane

12


13/26

Biochemical classes of drug targets:

13


14/26

Case study : Schizophrenia

Schizophrenia occurs with regular frequency nearly every wherein 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 adisintegration of the process of thinking and of emotional

responsiveness.

14


15/26

Schizophrenia

Complications:

Suicide5-10% of deaths

Depression- occurs in 50% of cases, often

after an acute episode Homelessness30-35% of homeless

Crime: 4-fold increase in acts of violence

compared with the general population. Thesepatients are more frequently victims of both

violent and nonviolent crimes.

Substance abuse

15


16/26

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

16


17/26

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 linkedmore than one gene may predispose people to it

there is currently no reliable way to predict whether

a person will develop the disease.

17


18/26

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 D2dopamine 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)

18


19/26

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 theworld's population, 30 % of whom do not respond to currently

available treatments.

19


20/26

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

20


21/26

(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.

21


22/26

(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 andhumans.

22


23/26

NEUROSTEROID AND SIGMA RECEPTORS

It is well documented that sigma1 receptor ligandsincrease the NMDA receptor response in the

hippocampus, suggesting a role in enhancing cognition.

Neurosteroids, such as dehydroepiandrosterone

(DHEA) and allopregnanolone, have been implicated inneuroprotection and enhancement of NMDA receptor

neurotransmission, possibly through interaction with

sigma1 receptors, suggesting therapeutic potential for

enhancing cognition in schizophrenia.

23


24/26

2-ADRENERGIC RECEPTORS

The central noradrenergic system projects from the locusceruleus 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 adrenergicreceptor 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 thatcan improve cognition.

24


25/26

SUBEROYLANILIDE HYDROXAMIC ACID ( SAHA)

An enzyme called HDAC2 ( histone deacetylase 2) was highly

expressed in the brain of mice chronically treated withantipsychotic 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.

25


26/26

26

Documents

Schizophrenia (3)