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

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

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

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

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

MECHANISM OF ACTION

Classes

Class I nuclear receptors

Class II nuclear receptors

Class III nuclear receptors

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

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

CHEMICAL TRANSMISSION AND DRUG ACTION IN THE CNS

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:

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,

Adrenaline, controls the eyes and little bit dryness

of mouth

CHEMICAL SIGNALING IN THE CNS

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

TARGETS FOR DRUG ACTION

Targets for drug action

Receptors Enzymes Ion channels Carrier Molecules

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

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

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

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

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

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

END