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
Extracellular fluid
Cell membrane
Few ex. of free receptors in cytoplasma
Cytoplasma
Organelles
Cell
Nucleus
Drugs that do act on receptors:
Drugs that do not act on receptors:
Acetylcholin
(Neurotransmittor)
Antacida: CaCO3 + HCl
ca. 5Å
Acetylcholin Agonists
Diuretica (osmotic)
O
Pilocarpine
Carbacholin
N
O
Me
N
O
Akylating agents (cancer)
O
H
H2N
O
N
O
O
Cl
Cl
Cl
Cl
N
Nu
N
Acetylcholin Antagonists
N
Nu
Atropin
N
Psoralenes
N
O
O
O
N
O
NH2
R
O
O
R'
O
N
HN
h
N
N
OH
O
HN
Cyclopentolat
O
N
R
O
O
O
R'
O
O
O
NH2
N
OH
O
Agonist:
Binds to (have affinity for) receptor
Binding leads to biolog. responce
(Agonists have intrinsic activity / efficacy)
Antagonist:
Affinity for receptor
No intrinsic activity
N
H
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
Acetylkolin-esteras e
N
O
O
Kolin Acyltransferas e
Acetylkolin
(AcCh)
Synapse
Nerve cell
Effector celle
reseptor
Nerve potensial
AcCh
AcCh
AcCh
AcCh (exess)
Ch-acetyltransferase
Ch
AcCh-esterase
Ch
N
Kolin
(Ch)
OH
Reversible inhibitors
O
AcCh
OH
O
N
O
O
k3(AcCh)
OH
O
OH
N
HO
O
OH
Inhibitor
Me2N
O
O
R
O
k3(inhibitor)
NMe2
OH
O
Me2N
HO
OH
R
More difficult to cleave
Reversible inhibitor (drugs): k3 (inhib) < k3(AcCh)
Neostigmin
Pyridostigmin
N
Myastenia gravis (weak muscles, reduced sensitivity to Acetylcholine)
O
O
O
N
N
O
N
Irreversible Inhibitors
Not drugs, nerve gasses, insecticides etc.
Gen structur mustard gasses
L
R2
P
O
R1
N
O
L: Leaving group
R1: alkoksy
R2: alkyl, alkoksy, amino
N
P
F
O
P
O
O
O
O
O
O
Sarin
Tabun
OH
O
Aging
OH
R2
P
O
OR
O
P
R1
O
not tox.
Act as mustard gasses
Pralidoxim
OH
HO
N
L
R1
N Me
Pralidoxim
motgift
OH
OR
O
P
R1
O
N
N Me
O
Malaoxon
P
O
R1
OH
only insects
O
P
O O
S
O
O
Malation
OR
L
O
O
S
P
O S
P
OR
O
Ionic bond
5-10 kcal/mol,
Reversible bonding
Hydrogen bond
2-5 kcal/mol,
Reversible bonding
Hydrophobic interaction
0.5-1 kcal/mol,
Reversible bonding
Acetylcholin
O
O
O
O
H
N
O
O
N
H
Anion
cavity
N
Lipophilic area
H
H-bind acceptor
HO
O
OH
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:
Agonist
Receptor
Conformation A
No ligand bound
+ Agonist
Responce
Conformation B
+ Antagonist
Antagonist
ConformationA
or
Inactive conformation C
The macromolecular pertubation theory:
(induced fit + rate theory)
Responce
The activation -agregation theory:
Always dynamic equilibr.
Agonist
Responce
+ Agonist
Responce
Conformation B
(Active)
Antagonist
+ Antagonist
Responce
Inv. Agonist
Responce B
(opposite of responce A)
Responce A
+ Inverse agonist
Dose-Responce Relationships
[A] - equil. towards AB
A-B
A + B
L-R
L + R
[L] - equil. towards LR ??
L
L-R
R locked in membrane (do not move freely)
L dissolved in extracellular fluid
R
Reaction on solid - liquid interface
Biological responce
% biolog. effect
% biolog. effect
100
100
50
50
EC50
EC50
[Agonist ligand]
log [Agonist ligand]
biolog. effect
X
Y
Efficacy (how high activity is possible)
Efficacy X = Efficacy Y (both can give 100% responce)
Z
Efficacy X> Efficacy Z (Z cam only give ca 30% responce)
EC50 X and Y
Potency (how easily is a given responce reached
(ex EC50)
EC50 Z
Potency X > Potency Y
Potency X = Potency Z
Potency Z > Potenzy Y
log [Agonist ligand]
Types of receptors
Superfamily
Endogenous
ligands
General structures
1
Fast neurotransmittors
ex. Acetylcholine
Ligand gated ion chanels
2
Slow neurotransm. ex. noradrenalin
Hormones
G-Protein coupled receptors
3
Insuline
Growth factors
Enzyme coupled receptors
Catalytic receptors
4
Steroid hormones
Thyreoid hormones
Vitamin A, D
Cytoplasmic receptors
Ligand gated ion chanels
Ligand binding sites
Ligands
Fast neurotransmittors
ex. Acetylcholine (nicotinic reseptors)
Membrane
(Phospholipides)
Ion chanel
Fastest intracellular responce, ms
Binding of ligand - opening of chanel - ion (K+, Na+) in or out of cell - responce
Nobel prize chemistry 2003,
Roderick MacKinnon “for structural and mechanistic studies of ion channels”.
http://nobelprize.org/chemistry/laureates/2003/press.html
G-Protein coupled receptors
G-protein: Guanine nucleotide binding protein
Ligand
(Agonist)
Extracellular fluid
Target
Intracellular fluid
Conform. change
Reseptor

GDP
G-protein
GTP

+P



GDP
GDP


O
HN



N
N
H 2N
N
O
O
O P O P O
O
O
O
n
HO OH
GTP
Responce
n=1; GDP
n=2; GTP
GTP
Subtypes of G-proteins - Targets (Second messenger systems)
Ion chanels: G12 Na+ / H+ exchange
Enzyms:
Gi Inhib. Adenylyl cyclase
Gs Stimul. Adenylyl cyclase
Gq Stimul. Phospholipase C
One ligand can bind to more than one type of G-prot. coupled reseptors
second messenger pathways
NH2
NH2
N
N
Adenylyl cyclase
O
P O P
ATP
OH
N
N
N
O
O
O
N
O P O P O P O
O
O
O
O
HO
N
N
O
O P O
O
OH
c-ATP
Activate c-AMP dependent protein kinases
(Phosphoryl. of proteins, i.e. enzymes)
Various responces
(ex. metabolism, cell division)
Subtypes of G-proteins - Targets (Second messenger systems)
Ion chanels: G12 Na+ / H+ exchange
Enzyms:
Gi Inhib. Adenylyl cyclase
Gs Stimul. Adenylyl cyclase
Gq Stimul. Phospholipase C
Various processes in cell
Various processes in cell
second messenger pathways
Release Ca2+
Activate protein kinases
O
R
R'
O
O
Phopholipase C
O
O
O
O
P O
OH
O
HO
HO
R
O
O P O
OH
O
O
+
HO
HO
O
P
O
O
OH
O
O
R'
O
P
P
DAG
Diacylglycerol
IP3
Inositol-1,4,5-triphosphate
P
PIP2
Phosphatidylinositol besphophate
Several steps
Li
(Treatmen manic depression)
Enzyme coupled receptors - Catalytic receptors
Ligands: Peptide hormones
1) Binding of Ligand
2) Dimerisation
of reseptor
Tyr kinase
-OH
domain
(Janus kinase)
Phosphoryl of Tyr
-OH
-OH
STATS
protein
O P
O P
O P
O P
STATS
protein
STAT: Signal transducers and activators of transcription
1) Phosphoryl. of STAT
2) Release of STAT in cytoplasma
3) STATto cell nucleus
4) Intitation of transcription
Cytoplasmic receptors
(not bound to cell membranes)
Lipophil. ligand thru cell membrane
Cell membrane
Cytoplasma
Responce
Cell nucleus
HSP-90
Protein
DNA
HSP-90
DNA
(HSP-90: Heat shock protein)
mRNA
Receptor subtypes
Most receptor classes - several sub-types
Each subtypes - differend A(nta)gonists
Sub types cholinerge reseptors
Det somatiske nerves ystem
Det autonome nervesys tem
CNS
Det sympatiske Det paras ympatis ke
nervesystem
nervesystem
CNS
CNS
Acetylcholin
(Neurotransmittor)
ganglion
Acetylkolin
ca. 5Å
Noradrenalin
O
Synapse
O
N
Reseptor
O
Effektor celle
H
Muscarinerge
receptors
M1: G-Protein coupled receptors
Stimulate phopholipase A
4.3 Å
HO
O
O
Nicotinerge
receptors
N
Nmuscle: Ligand gated ion chanels
5.9 Å
M2: G-Protein coupled receptors
Inhib. adenylyl cyclase
Incr. Na+/Ca2+
N
H
H
N
O
H
Nneuro: Ligand gated ion chanels
Incr. Na+/Ca2+
Spare receptors - Partial agonist
Full agonist
Full responce
Spare receptors
Partial agonist
Weak responce
Full responce
Responce
= Agonist
Absens of full agonist
Responce
Presence of full agonist
= Antagonist
Desensitizing
Receptor and normal amount of ligand = agonist
Overstimulated receptor
Sensitizing
Receptor and normal amount of ligand = Antagonist
Overstimulated receptor