Molecular Targets For Drug Action (syllabus -prof.Kršiak)

FOUR MAJOR TARGETS FOR DRUGS:

1. RECEPTORS

2. ION CHANNELS

3. CARRIER MOLECULES

4. ENZYMES

Molecular Targets For Drug Action

FOUR MAJOR TARGETS FOR DRUGS:

1. RECEPTORS

2. ION CHANNELS

3. CARRIER MOLECULES

4. ENZYMES

RECEPTORS

Cell Membrane

Intracellular - Receptors linked to gene transcription (nuclear receptors)

Channel-linked receptors

G-protein-coupled receptors

Kinase-linked receptors

1. RECEPTORS

- about 90% of synapses in the CNS- for fast synaptic transmission (msec)- examples:

NICOTINIC, NMDA RECEPTOR: Na+ flows into cells, depolarization, excitation

GABAA RECEPTOR:Cl- flows into cells, hyperpolarization, inhibition

CHANNEL-LINKED RECEPTORS(„ionotropic receptors“)

CHANNEL-LINKED RECEPTORS(„ionotropic receptors“)

Katzung 2-12 ale raději GABAA

Katzung BG, 2001

Nicotinic receptor

pentameric structure - five subunits form a cluster surrounding a central transmembrane pore. When acetylcholine binds, the channel pore opens.

Remedia 1998

Cl-

Cl-- pentameric structure- receptor for GABA, for modulatory drugs (eg. benzodiazepines)

CHANNEL-LINKED RECEPTORS(„ionotropic receptors“)

GABAA receptor

Benzodiazep. receptor

- sites for action of about 45% of drugs- for slow synaptic transmission (seconds - minutes)-examples: beta-adrenergic receptors,

muscarinic receptors- „coupling“:

RECEPTOR - serpentine receptors: a polypeptide chain traverses the membrane seven times

G PROTEIN

EFFECTOR

G-PROTEIN-COUPLED RECEPTORS(„metabotropic receptors“)

G-PROTEIN-COUPLED RECEPTORS(„metabotropic receptors“)

Katzung Fig 2-14

Katzung BG, 2001serpentine receptors: a polypeptide chain traverses the membrane seven times, the extracellular terminal (NH2), the intracelullar carboxyl terminal, sites for binding ligands, G-protein

G-PROTEIN-COUPLED RECEPTORS(„metabotropic receptors“)

RECEPTOR

G PROTEIN - trimer, , , subunits subunit: GDPGTP, GTPase aktivity

stimulation (GS) , inhibition (GI) of the effector

EFFECTOR

betagama

EFFECTOR

AlfaGDPGTP

AlfaAlfaGTPGTP

AlfaGDP

EFFECTOR RECEPTORG-PROTEIN

AlfaGDP

G-PROTEIN-COUPLED RECEPTORS(„metabotropic receptors“)

eg. adenylyl cyclase

Gs beta-adrenergic receptor

Gi mu opioid receptor

AlfaGDP

EFFECTOR

EFFECTOR

ENZYM

adenylyl cyklase cAMP

fosfolipase C IP3, DAG Pro

tein

kina

ses

G-PROTEIN-COUPLED RECEPTORS(„metabotropic receptors“)

G-PROTEIN

RECEPTOR

Ca++ release

2nd messengers:

Activation/inhibition of cellular functionseg. contractile proteins, enzymes, transporters, ion channels

ION CHANNEL

Molecular Targets For Drug Action)

FOUR MAJOR TARGETS FOR DRUGS:

1. RECEPTORS

2. ION CHANNELS

3. CARRIER MOLECULES

4. ENZYMES

2. ION CHANNELS

• voltage-gated channels

calcium channels - Ca++ flows into cells, calcium channel blockers

sodium channels - Na++ flows into cells, blocked by local anaesthetics

ligand-gated channels, G protein-gated*, and other*(directly or by intermediaries),

Molecular Targets For Drug Action

FOUR MAJOR TARGETS FOR DRUGS:

1. RECEPTORS

2. ION CHANNELS

3. CARRIER MOLECULES

4. ENZYMES

3. CARRIER MOLECULES

• „pumps“

sodium pump - Na+/K+ ATPase,

„pumps“ Na+ from the cell, inhibited by cardiac glycosides

proton pump - H+/K+ ATPase,

„pumps“ H+ from the cell , proton pump inhibitors

• transporters transporters for noradrenaline, serotonine inhibited by most antidepressants (RUI, TCA, SSRI etc)

Molecular Targets For Drug Action

FOUR MAJOR TARGETS FOR DRUGS:

1. RECEPTORS

2. ION CHANNELS

3. CARRIER MOLECULES

4. ENZYMES

4. ENZYMESsites of action of about 30% of drugs

Drugs inhibiting the enzyme:

Cholinesterase Cholinesterase Inhibitors

Cyclo-oxygenase Non-Steroid Antiinflammatory Drugs

Monoamine oxidase IMAO

Angiotensin- converting enzyme

ACE Inhibitors

HMG-CoA reduktase Statins

and other

G-protein coupled receptorsmembr.

Voltage gated- Calcium chan.

- Sodium chan.

„pumps“- sodium

- proton

transporters

cardiac glykosides

PP inhibitors

lok. anaesthetetics

Calcium ch. blockers

about 45% of drugs,e.g. beta-blockers

antidepressants

ACE inhibitors, IMAO

perif. muscle relaxants

Examples of drugs::

Enzyme-linked rec.intracelul.

Ligand-gated, G-prot.,…

ACE, MAO, COX, HMG-CoA reductase

Channel-linked receptors

1. RECEPTORS

2. ION CHANNELS

3. CARRIER MOLECULES

Molecular mechanisms of drug effects - summaryFOUR MAJOR TARGETS FOR DRUGS:

4. ENZYMES