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Receptors and Drug Action
Receptors:
Specific areas of cell membranes (proteins, glycoproteins)*
When bound to ligand, positive or negative biological responce
Ligand
cellmembrane with receptor
Biological responce
Few ex. of free receptors in cytoplasma CellNucleus
Cell membrane
Organelles
Cytoplasma
Extracellular fluid
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Drugs that do not act on receptors:
Antacida: CaCO3 + HCl
Diuretica (osmotic)
Akylating agents (cancer)
ClN
ClN
Cl
Nu
N
Cl
Nu
Drugs that do act on receptors:
NO
O
OH
ca. 5
Acetylcholin(Neurotransmittor)
NO
O
H2N
Carbacholin
N
N
Me
H
OO
Acetylcholin Agonists
Pilocarpine
Acetylcholin Antagonists
N
O
O
OH
Atropin
O
O
N
OH
Cyclopentolat
OO O
R
R'
HN
N
O
O
OO O
R
R'
HN
N
NNO
O NH2
ONN
NH2
O
h
Psoralenes
Agonist:Binds to (have affinity for) receptor
Binding leads to biolog. responce
(Agonists have intrinsic activity / efficacy)
Antagonist:
Affinity for receptor
No intrinsic activity
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Binding of ligand to receptor
Covalent bond
Ionic bond
Hydrogen bond
Hydrophobic interaction
Covalent bond
strong; 50-150 kcal/mol,
Normally irreversible bonding
ex. Acetylcholine esterase inhibitors
Effector celleSynapse
reseptor
AcCh
Nerve potensial
AcCh
AcCh (exess)
AcCh-esterase
Ch
ChCh-acetyl-transferase
AcCh
Nerve cell
N O
O
Acetylkolin(AcCh)
Acetylkolin-esterase
Kolin Acyltransfe rase
N OH
Kolin(Ch)
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Reversible inhibitors
OH O O
OH O
OH
NO
O
NHO
k3(AcCh)
AcCh
Inhibitor
Neostigmin Pyridostigmin
Myastenia gravis (weak muscles, reduced sensitivity to Acetylcholine)O
N O N
O
N O N
OHO O
NMe2OH O
Me2N OH
RO
O
Me2N
RHO
k3(inhibitor)
More difficult to cleave
Reversible inhibitor (drugs): k3(inhib) < k3(AcCh)
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Irreversible Inhibitors Not drugs, nerve gasses, insecticides etc.
L
PO
OR
R2
OH O POH
L
OR
R1O
HO
PO
OR
R1
Aging
OP
OH
R1 O
Pralidoxim
N
N
OH
Me
OH
Pralidoxim
motgift
N
N
O
Me
P
O OR
R1
Gen structur mustard gasses
P
O
O
N
N
Tabun
FP
O
O
Sarin
LP
O
R1
R2
L: Leaving groupR1: alkoksyR2: alkyl, alkoksy, amino
O
O
O
O
SP
S
O
O
Malation
only insects
O
O
O
O
SP
O
O
O
Malaoxon
Act as mustard gassesnot tox.
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Ionic bond
5-10 kcal/mol,
Reversible bonding
NO
O
OH
Acetylcholin
Hydrogen bond
2-5 kcal/mol,
Reversible bonding
NO
O
O H
Hydrophobic interaction
0.5-1 kcal/mol,
Reversible bonding
OHO
NH
OH
Anion
cavity
H-bind acceptor
Lipophilic area
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The occupancy theory:
The more receptors sites occupied by ligand, the stronger responce
The rate theory:
The more ligand-receptor interact / unit time, the stronger responce
The induced-fit theory:
ReceptorConformation ANo ligand bound
+ Agonist
Agonist
Responce
+ Antagonist
Conformation B
AntagonistResponce
ConformationAorInactive conformation C
The macromolecular pertubation theory:
(induced fit + rate theory)
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The activation -agregation theory:
Conformation B(Active)
Responce
Always dynamic equilibr.
Responce+ Agonist
Agonist
Responce+Antagonist
Antagonist
Responce A+Inverse agonist
Inv. Agonist
Responce B(opposite of responce A)
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Dose-Responce Relationships
A + B A-B [A] - equil. towards AB
L + R L-R [L] - equil. towards LR ??
L
Biological responce
R
L-R R locked in membrane (do not move freely)
L dissolved in extracellular fluid
Reaction on solid - liquid interface
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[Agonist ligand]
% biolog. effect
50
100
EC50
log [Agonist ligand]
% biolog. effect
50
100
EC50
log [Agonist ligand]
biolog. effect
X Y
Z
Efficacy X = Efficacy Y (both can give 100% responce)
Efficacy X> Efficacy Z (Z cam only give ca 30% responce)
Efficacy (how high activity is possible)
Potency (how easily is a given responce reached
(ex EC50)
Potency X > Potency YPotency X = Potency ZPotency Z > Potenzy Y
EC50X and Y
EC50Z
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Types of receptors
Super- Endogenous General structures
family ligands
1 Fast neurotransmittors Ligand gated ion chanels
ex. Acetylcholine
2 Slow neurotransm. ex. noradrenalin G-Protein coupled receptors
Hormones
3 Insuline Enzyme coupled receptors
Growth factors Catalytic receptors
4 Steroid hormones Cytoplasmic receptors
Thyreoid hormones
Vitamin A, D
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Ligand gated ion chanels
Fastest intracellular responce, s
Binding of ligand - opening of chanel - ion (K+, Na+) in or out of cell - responce
Ligands
Fast neurotransmittors
ex. Acetylcholine (nicotinic reseptors)
Nobel prize chemistry 2003,Roderick MacKinnon for structural and mechanistic studies of ion channels.
http://nobelprize.org/chemistry/laureates/2003/press.html
Membrane(Phospholipides)
Ion chanel
Ligand binding sites
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G-Protein coupled receptors G-protein: Guanine nucleotide binding protein
Extracellular fluid
Intracellular fluid
Ligand(Agonist)
ReseptorConform. change
GDP
GTP
G-protein
GDP
GTP
Target
GTP
GDP+ P
Responce
HN
N N
N
O
OOP
O
O
OP
O
O
O
OHHO
n=1; GDPn=2; GTP
n
H2N
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Subtypes of G-proteins - Targets (Second messenger systems)
Ion chanels: G12Na+/ H+exchange
Enzyms: GiInhib. Adenylyl cyclase
GsStimul. Adenylyl cyclaseGqStimul. Phospholipase C
One ligand can bind to more than one type of G-prot. coupled reseptors
second messenger pathways
N
N N
N
NH2
OOP
O
O
OP
O
O
OP
O
O
O
OHHO
ATP
Adenylyl cyclase
P O P
N
N N
N
NH2
O
OH
c-ATP
OP OO
O
Activate c-AMP dependent protein kinases (Phosphoryl. of proteins, i.e. enzymes)
Various responces(ex. metabolism, cell division)
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Subtypes of G-proteins - Targets (Second messenger systems)
Ion chanels: G12Na+/ H+exchange
Enzyms: GiInhib. Adenylyl cyclase
GsStimul. Adenylyl cyclaseGqStimul. Phospholipase C
second messenger pathways
Phopholipase C
O
O
HOHO
OOH
P
P
PO
O
O
O
O
O
R'
O
R
PIP2Phosphatidylinositol besphophate
O
O
HOHO
OOH
P
P
P
OH
O
O
O
O
O
R'
O
R
O
+
IP3Inositol-1,4,5-triphosphate
DAGDiacylglycerol
Activate protein kinases
Various processes in cell
Release Ca2+
Various processes in cell
Several steps Li (Treatmen manic depression)
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Enzyme coupled receptors - Catalytic receptors
1) Binding of Ligand2) Dimerisation
of reseptor
-OH -OH -OHTyr kinasedomain(Janus kinase)
Phosphoryl of Tyr
O P O P
STATSprotein
O P O P STATSprotein 1) Phosphoryl. of STAT2) Release of STAT in cytoplasma3) STATto cell nucleus4) Intitation of transcription
STAT:Signal transducers and activators of transcription
Ligands: Peptide hormones
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Cytoplasmic receptors
(not bound to cell membranes)
DNA
DNAmRNA
Protein
Responce
HSP-90
Cell membrane
Cytoplasma
Lipophil. ligand thru cell membrane
HSP-90
Cell nucleus
(HSP-90: Heat shock protein)
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Receptor subtypes
Most receptor classes - several sub-types
Each subtypes - differend A(nta)gonists
Sub types cholinerge reseptors
Nicotinerge
receptors
Muscarinerge
receptors
O H
N
N
HO
H
O
HO
N
CNS
Effektor celleRese ptor
Synapse
Acetylkolin
Noradrenalin
Det somatiske nervesystem Det autonome nervesystem
CNS CNS
Det sympatisk enervesystem
Det parasympatisknervesystem
ganglion
4.3
5.9
M1: G-Protein coupled receptors
Stimulate phopholipase A
M2: G-Protein coupled receptors
Inhib. adenylyl cyclase
Nmuscle: Ligand gated ion chanelsIncr. Na+/Ca2+
Nneuro: Ligand gated ion chanels
Incr. Na+/Ca2+
NO
O
OH
ca. 5
Acetylcholin(Neurotransmittor)
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Full responce
Spare receptors
Full agonist
Weak responce
Partial agonist
Full responce
Spare receptors - Partial agonist
Absens of full agonist
Responce = Agonist
Presence of full agonist
Responce = Antagonist
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Desensitizing
Sensitizing
Receptor and normal amount of ligand = agonist
Overstimulated receptor
Receptor and normal amount of ligand = Antagonist
Overstimulated receptor