Nuclear Receptor and Drug Action in CNS

2. NUCLEAR RECEPTOS & CHEMICAL TRANSMISSION AND DRUG
ACTION IN THE CNS
Introduction
Structure
Mechanism of
Action
Classification of
Psychotropic Drug
Targets for Drugs
Action
Drug in CNS

3. NUCLEAR RECEPTORS
“Nuclear receptors are a family of highly conserved transcription in response to small
lipophilic compound.”
Play important role in development, physiology and disease in humans by regulating
gene expression (Protein or amino acid formation)
Estrogen or β-estradiol act upon the nuclear receptor to regulate gene expression for
Female Sex Development
Testosterone or Androgens act upon nuclear receptors to regulate gene expression for
Male Sex Development

4. STRUCTURE
All nuclear are monomeric proteins
Share broadly similar structural design
It has six domains (A-F):
(A-B) N-regulatory domain
(C) DNA binding domain
(D) Hinge Region
(E) Ligand binding domain
(F) C-terminal domain

5. STRUCTURE
(A-B) N-regulatory domain: Highly variable in sequence between various nuclear receptors
(C) DNA binding domain: Highly conserved, contain two zinc fingers that bind to specific DNA sequences
(D) Hinge Region: Flexible domain
(E) Ligand binding domain: it is alpha helical sandwich fold, three anti-parallel helices flanked by two alpha helices on
one side and three on the other, binding cavity is within the inferior of the LBD and just below three anti-parallel alpha
helical sandwich
(F) C-terminal domain: Highly variable sequence, Near to it are located the motifs that contain nuclear localization
signals

7. FUNCTIONS OF THE DOMAINS
N-terminal domain: harbors AF1 site that binds to other cell specific transcription factors in a
ligand-independent way and modifies the binding or activity of the receptor
DNA binding domain: Binds to the specific sequences of DNA called hormone response element
Hinge region: Connects the DNA binding domain to the ligand binding domain
Ligand binding domain: Harbors the AF2 whose action depends upon the bound ligand
C-terminal domain: has ability to the transcription

8. MECHANISM OF ACTION
Classes
Class I nuclear
receptors
Class II nuclear
receptors
Class III nuclear
receptors

9. MECHANISM OF ACTION
Class I Nuclear Receptors: Largely steroid receptors
Ligands are mainly steroids
Located in cytoplasm or attached to cytoskeleton or other structures
When ligand binds, form homodimers in the presence of their partners and migrate to nucleus
to trigger signal response
A single ligand can regulate a large number of genes

10. MECHANISM OF ACTION
Class II Nuclear Receptors: Their ligands are mainly lipids
Located in nucleus
They form heterodimers with retinoid X receptors
Class III Nuclear Receptors: They transduce endocrine signals but function
as heterodimers

12. CHEMICAL TRANSMISSION AND DRUG ACTION IN THE CNS

13. INTRODUCTION
• Drugs acting on CNS are of special significance and
of major therapeutic use but also the drugs which are
commonly administered for non-medical reasons like
coffee, tea and nicotine
• CNS is functionally more complex. Behavior of drug
on the individual cell of brain is different from the
whole brain unlike the other organs
Two reasons for
understanding
the action of
drugs on CNS is
difficult:

14. CHEMICAL SIGNALING IN THE CNS
CNS produce neurotransmitter
which start processes in the body
and control the biological
functions
It is important to study the
physiology of brain and to study
chemical signaling because whole
body is linked with it.
Drug acting upon CNS will also
produce effects on the body.
For Example,

15. Adrenaline, controls the
eyes and little bit
dryness of mouth
Dopamine, disturbance
in its release leads to
Parkinson’s disease
GABA, is related to
anxiety
CHEMICAL SIGNALING IN THE CNS

16. CHEMICAL SIGNALING IN THE CNS
Neurotransmitters control various process in the body in a range of different time scales. The time scale may be in
Miliseconds
Minutes
Hours
Days
Months
Year
Brain system works like a candy floss into the grand canyon
Candy floss mean number of threads that are placed on a stick and enter into a grand canyon

18. TARGETS FOR DRUG ACTION
Targets for
drug action
Receptors Enzymes Ion channels
Carrier
Molecules

19. Receptors
• A protein that recognizes the body’s natural mediator or the drug
• When ligand will bind, it transmits signal and elicits a biological effect
Ion channels
• Ion channels are proteins in membrane that allow passage of specific ions only when activated
• Upon receiving signals, it will open and allows the ions to pass
Enzymes
• Biological catalysts that speed up chemical reaction without being changed
• Many drugs act by inhibiting the action of enzymes
Carrier molecules
• Membrane bounded proteins that transport specific molecules
• Molecule to be transported binds to specific protein for recognition site on the carrier and then molecule is transferred to other
side of membrane
TARGETS FOR DRUG ACTION

20. DRUG ACTION IN CNS
Study action of drug on brain is difficult due to complexity of neuronal
interconnections in the brain
Difficult to predict effects of blocking or enhancing release or action of
one or other neurotransmitters greatly depend upon
External inputs
Influence of glial cells
Range of secondary adaptive responses
Blood brain barrier

22. Drug transport to specific
target in brain
Direct penetration
Small non-polar molecules
diffuse passively across cell
membrane
Penetration via
transporters
Transporters facilitate entry
into brain
DRUG ACTION IN CNS

23. CLASSIFICATION OF PSYCHOTROPIC DRUGS
Anaesthetic
agents
• Used to produce surgical anesthesia
• For example, halothane, propofol
Anxiolytic
and
Sedatives
• Used to induce sleep and reduce anxiety
• Hypnotics, sedatives, minor tranquilizers
• For example, barbiturates, benzodiazepines
Antipyschoti
cs drugs
• Used to relieve schizophrenic illness
• Neuroleptics, major tranquilizers
• Clozapine, chlorpronazine
Antidepressa
nt drugs
• Used to relieve depressive illness
• Thymoleptics
• Escitalopram

24. Analgesic drugs
• Used to relieve from pain
• For example, opiates and carbamazepine
Psychomotor
stimulants
• Used to induce wakefulness and euphoria
• Psychostimulants
• For example, amphetamine, cocaine, caffeine
Psychotomimetic
drugs
• Used to cause disturbance of perception
• Hallucinogens, psychodysleptics
• For example, mesacline, phencyclidine
Cognition
enhancers
• Used to improve memory and cognitive performance
• Nootropic drugs
• For example, tacrine, donepezil
CLASSIFICATION OF PSYCHOTROPIC DRUGS

25. Some drugs defy this classification
For example, lithium, dissociative anesthetic, used in the
treatment of manic depressive psychosis and ketamine
It produces psychotropic effect rather similar to those produced
by phecyclidine
CLASSIFICATION OF PSYCHOTROPIC DRUGS