Nuclear Receptor and Drug Action in CNS

1. NUCLEAR RECEPTORS
Introduction:
“Nuclear receptors are a family of highly conserved transcription in response to small lipophilic compound.
They play a role in every aspect of development, physiology and disease in human.
It is of great importance because the disease related to development and physiology of human which is
regulated by nuclear receptors can be treated. For example, steroid hormones act upon the nuclear receptors.
Β-estradiol or estrogen control female sex development and it acts upon the nuclear receptors to regulate
gene expression. Similarly, testosterone or androgens control male sex development by acting upon the
nuclear receptors to regulate gene expression.
Structure:
All nuclear receptors are monomeric proteins that share a broadly similar structural design. A nuclear has
the six domains (A-F):
 (A-B) N-regulatory domain: It is highly variable in sequence between various nuclear receptors
 (C) DNA binding domain: It is highly conserved domain containing two zinc fingers that binds to
specific sequences DNA
 (D) Hinge region: It is a flexible domain.
 (E) Ligand binding domain: There is an alpha helical sandwich fold in which three anti parallel
alpha helices (the "sandwich filling") are flanked by two alpha helices on one side and three on the
other (the "bread"). The ligand binding cavity is within the interior of the LBD and just below three
anti parallel alpha helical sandwich "filling"

 (F) C- terminal domain: It highly variable sequence in various receptors. Near to it are located the
motifs that contain nuclear localization signals.
The N-terminal, DNA binding and ligand binding are independently well folded and structurally stable.
Hinge region and C-terminal domains may be conformationally flexible and disordered.

2. Functions of the domains:
 N-terminal domain: It habours the AF1 (Activation Function 1) site that binds to other cell specific
transcription factors in a ligand-independent way and modifies the binding or activity of the receptor
itself
 DNA binding domain: It binds to the specific sequences of DNA called hormone response element
 Hinge region: It is flexible domain that connects the DNA binding domain to the ligand binding
domain
 Ligand Binding Domain: It habours the AF2 (Activation Function 2) whose action is dependent
upon the bound ligand
 C-terminal domain: It has ability activate the transcription.
Mechanism of Action:
There are two main classes of the nuclear receptors:
1. Class I nuclear receptors
2. Class II nuclear receptors

3. Class I Nuclear Receptors:
It largely consist of receptors for steroid hormones. Their ligands are mainly endocrine or steroids. They
are located in cytoplasm attached to cytoskeleton or other structures. When ligand binds to a receptor, they
form homodimers in the presence of their partner and migrate nucleus to trigger the signal response. In this
way, a single ligand regulate a large number of genes.
Class II Nuclear Receptors:
Their function is slightly different way. Their ligand are mainly lipids. They are present in the nucleus.
They form heterodimers with retinoid X receptors.
Class III Nuclear Receptors:
The third subgroup, Class III Nuclear Receptors transduce endocrine signals but function as heterodimers.
General Mechanism of Signal Response
Once in the nucleus, the ligand bound receptors recruits futher proteins including co-activators or co-
repressors to modify gene expression through it AF1 and AF2 domains. The co-activators are enzymes
involved in regulation of DNA transcription. The co-repressors are composed of enzymes which prevent the
DNA transcription.
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CHEMICAL TRANSMISSION & DRUG ACTION IN THE C.N.S
Introduction:
There are two reasons for understanding the action of drugs on CNS is difficult:
1. Drugs acting on CNS are of special significance because they are not only of major therapeutic use
but also the drug which are commonly administered for non-medical reasons like tea, coffee, and
nicotine.
2. CNS is functionally far more complex than any other system in the body due to which understanding
of drug effects is much difficult. The behavior of drug on the individual cell of brain is different
from the organ as a whole while in other body organs (heart, kidney, etc.) studying the effect of drug
on cells gives us clear idea of how it affects the organ.
Chemical Signaling in the CNS:
The CNS produce neurotransmitters which start processes in the body and control the biological functions.
Acetylcholine, GABA, and many other neurotransmitters produced in the brain are very important.
It is very important to study the physiology of brain and to study the chemical signaling in the CNS because
brain system is very complex and the whole body is linked with it. The drug acting upon the CNS will also
produce effects on the body.

4. For example, adrenaline is a neurotransmitter released from CNS directly controls the eyes and little bit
dryness of mouth.
Dopamine is a neurotransmitter released from CNS. The disturbance in its release directly leads to
Parkinson’s disease.
Number of neurotransmitters released from brain produce action on the kidneys and heart.
GABA neurotransmitters released from CNS are related to anxiety.
Number of neurotransmitters control various processes in the body in a range of different time scales. The
time scale may in milliseconds, minutes, hours, days, months and year.
The brain system work like candy floss into the grand canyon. Candy floss mean number of thread that are
placed on a stick and enter into a grand canyon.
Targets For Drug Action:
The action of drug on body is called pharmacodynamics.
When a drug enters the human body, it tends to stimulate certain Receptors, ion-channels or it act on
Enzymes, Carrier molecules. These are the protein targets for drug action.
 Receptors
 Ion-channels
 Enzymes
 Carrier molecules
Receptors

5. A receptor is a protein found in the body that acts as a recognition site for the body’s natural mediators or
ligands. A ligand will specifically bind to the receptor, which then transmits a signal and elicits a biological
effect. A ligand can switch this response on or off.
Once the receptors are activated, they either trigger a particular response directly on the body or they trigger
natural mediators or ligands, which then causes the release of hormones or other endogenous mediators in
the body.
For example, nicotinic acetylcholine receptors and their agonist is acetylcholine
Ion-channels
Ion-channels are proteins in the membrane that form a water filled pore or channel through which ions can
pass. They only allow specific ions to pass through them and only when activated.
Drugs can bind to ion-channels thereby altering its function For example, Local anesthetics that block
sodium ion channels.Ions are unable to penetrate the lipid bilayer of the cell membrane so they require ion-
channel to pass through.
Ion-channels are selective for particular ions which depend on the size of the pore and the nature of its
lining.
Enzymes
Enzymes are biological catalysts that speed up chemical reactions without being changed themselves.
An enzyme works by binding with substrate on active site in such a way that chemical reactions are induced
and products are formed.
Approximately half of the prescribed drugs act by inhibiting the action of specific enzymes. For example,
ASPRINE inhibits Cyclooxygenase enzyme that is required for prostaglandins to produce inflammation,
thus aspirin causes the reduction of inflammation.
Some drugs act as false substrate and drug molecule transfer to abnormal product that subverts the normal
metabolic pathway, For example, FLOURACIL that replaces uracil as an intermediate in purine synthesis
thus blocking DNA synthesis and preventing cell division.
Carrier molecules
Carriers are membrane bounded proteins that transport specific molecules. For example, ions and small
organic molecules such as glucose, across the plasma membrane to cell. The molecule binds to specific
recognition site on the carrier, this induces it to change and in doing so the molecule is transferred to other
side of membrane. For example, for potassium pumps(gastric mucosa) omeprazole is inhibitor and reuptake
of neurotransmitters.
DRUG ACTION IN CENTRAL NERVOUS SYSTEM:
Understanding how drugs effect brain function is made difficult by several factors. One is the complexity of
neuronal interconnections in the brain.

6. Diagram explanation
A noradrenergic neuron in the locus cerulues shown in dig as neuron 1 releasing transmitter a at its
terminal. Release of a effects neuron 2 which releases transmitter b and also effect neuron 1 by direct
feedback and indirectly by effecting presynaptic inputs on neuron 1. The firing pattern of neuron 2 also
effects the system party through interneuronal connections (neuron 3 releases transmitter c)
It is difficult to predict effects of blocking or enhancing the release or action of one or other transmitters and
it greatly depend on
Relative strength of the various excitatory and inhibitory synaptic connections
External inputs
Influence of glial cells
Range of secondary adaptive responses
Typically, an increase in transmitter release, or interference with transmitter reuptake, is countered by
inhibition of transmitter synthesis, enhanced transporter expression or decreased receptor expression. These
changes, which involve altered gene expression, generally take time (hours, days or weeks) to develop and are
not evident when drug effects are studied in acute experiments.
In the clinical situation, the effects of psychotropic drugs often take weeks to develop, so it is likely that they
reflect the adaptive responses rather than the immediate pharmacodynamic effects of the drug. For example
antidepressant drugs, antipsychotic drugs, opiates, benzodiazepines and psycho-stimulants. Therefore, its
important to study primary interactions of the drug with its target and also the secondary response of the brain
to this primary effect; it is often the secondary response, rather than the primary effect, which leads to clinical
benefit.
Blood brain barrier
Another important factor is the existence of the blood-brain barrier, penetration of which requires molecules
to pass through the vascular endothelial cells, rather than going between them.
Direct penetration
Only small non-polar molecules can diffuse passively across cell membranes.Some neuroactive drugs
penetrate the blood-brain barrier in this way,

7. Penetration via transporters
which can act either to facilitate entry into the brain or to diminish it by pumping the compound from the
endothelial cell interior back into the bloodstream. Examples include levodopa, valproate and various
sedative histamine antagonists. Drugs that are excluded include many antibacterial and anticancer drugs that
are substrates for the P-glycoprotein transporter
Classification of psychotropic drugs
Psychotropic drugs are defined as those that effect mode and behaviour, often used to treat anxiety depression
insomnia are mind altering drugs. As we know that brain is a very complex part of our body so there is no
consistent basis for classifying these drugs.
Following classification is based on that suggested in 1967 by world health organization WHO.
 Anaesthetic agents
Drugs used to produce surgical anaesthesia
E.g halothane propofol
 Anxiolytic and sedatives
Synonyms hypnotics sedatives minor tranquilizers
Definition drugs that cause sleep and reduce anxiety
E.g barbiturates, benzodiazepines
 Antipsychotic drugs
Synomyns
Neuroleptics, major tranquilizers
Drugs that are effective in relieving the symptoms of schizophrenic illness
E.g clozapine, chlorpronazine
 Antidepressant drugs
Synomyns thymoleptics
Drugs that alleviate the symptoms of depressive illness
E.g monoamine oxidase inhibitors and tricylic antidepressants
 Analgesic drugs
Drugs that used clinically for controllling pain
E.g opiates and carbamazepine
 Psychomotor stimulants

8. Synomyns psychostimulants
Drugs that cause wakefulness and euphoria
E.g amphetamine, cocaine caffeine
 Psychotomimetic drugs
Synomyns hallucinogens, psychodysleptics
Drugs that cause disturbance of perception and of bevaiour in ways that cannot be simply catagorized as
sedatives or stimulant effects
E.g lysergic acid diethylamide LSD, mescaline and phencyclidine
 Cognition enhancers
perhaps this is more of a wishful than a real category
Synomyms: nootropic drugs
Drugs that improve memory and cognitive performance
e.g tacrine, donepezil
Some drugs defy classification in this scheme, for example, lithium which is used in the treatment of manic
depressive psychosis and ketamine which is classed as a dissociative anaesthetic but produce psychotropic
effect rather similar to those produced by phencyclidine.
References:
1. Rang and Dale Pharmacology
2. Katzung Pharmacology
3. Lippincott Pharmacology
4. Pharmacology by Harry Beckman