Nuclear receptors and chemical action in cns
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Transcript of Nuclear receptors and chemical action in cns
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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
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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
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STRUCTUREAll 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
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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
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FUNCTIONS OF THE DOMAINSN-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
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MECHANISM OF ACTION
Classes
Class I nuclear receptors
Class II nuclear receptors
Class III nuclear receptors
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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
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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
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CHEMICAL TRANSMISSION AND DRUG ACTION IN THE CNS
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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:
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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,
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Adrenaline, controls the eyes and little bit dryness
of mouth
CHEMICAL SIGNALING IN THE CNS
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CHEMICAL SIGNALING IN THE CNSNeurotransmitters 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
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TARGETS FOR DRUG ACTION
Targets for drug action
Receptors Enzymes Ion channels Carrier Molecules
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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
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DRUG ACTION IN CNSStudy 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 inputsInfluence of glial cells
Range of secondary adaptive responses
Blood brain barrier
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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
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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
Antipyschotics drugs •Used to relieve schizophrenic illness•Neuroleptics, major tranquilizers•Clozapine, chlorpronazine
Antidepressant drugs •Used to relieve depressive illness•Thymoleptics•Escitalopram
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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
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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
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