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Receptors and Drug ActionReceptors: •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 cytoplasmaCell Nucleus
Cell membrane
Organelles
Cytoplasma
Extracellular fluid
Drugs that do not act on receptors:
Antacida: CaCO3 + HCl
Diuretica (osmotic)
Akylating agents (cancer)
ClN
ClN
Cl
NuN
Cl
Nu
Drugs that do act on receptors:
NO
O
OH
ca. 5Å
Acetylcholin (Neurotransmittor)
NO
O
H2N
Carbacholin
N
NMe
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
hν
Psoralenes
Agonist: Binds to (have affinity for) receptorBinding leads to biolog. responce (Agonists have intrinsic activity / efficacy)
Antagonist:Affinity for receptorNo intrinsic activity
Binding of ligand to receptor•Covalent bond•Ionic bond•Hydrogen bond•Hydrophobic interaction
Covalent bondstrong; 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 Acyltransferase
NOH
Kolin(Ch)
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)
Irreversible Inhibitors Not drugs, nerve gasses, insecticides etc.
L
PO
OR
R2
OH O POH
L
OR
R1O
HO
PO
OR
R1
Aging
O P
OH
R1O
Pralidoxim
N
N
OH
Me
OH
Pralidoximmotgift
N
N
O
Me
PO OR
R1
Gen structur mustard gasses
PO
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.
Ionic bond5-10 kcal/mol,Reversible bonding
NO
O
OH
Acetylcholin
Hydrogen bond2-5 kcal/mol,Reversible bonding
NO
O
OH
Hydrophobic interaction0.5-1 kcal/mol,Reversible bonding
OHO
NH
OH
Anion
cavity
H-bind acceptor
Lipophilic area
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)
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)
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
[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
EC50 X and Y
EC50 Z
Types of receptors
Super- Endogenous General structuresfamily ligands
1 Fast neurotransmittors Ligand gated ion chanelsex. Acetylcholine
2 Slow neurotransm. ex. noradrenalin G-Protein coupled receptorsHormones
3 Insuline Enzyme coupled receptorsGrowth factors Catalytic receptors
4 Steroid hormones Cytoplasmic receptorsThyreoid hormonesVitamin A, D
Ligand gated ion chanels
Fastest intracellular responce, s
Binding of ligand - opening of chanel - ion (K+, Na+) in or out of cell - responce
LigandsFast neurotransmittorsex. 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
G-Protein coupled receptors G-protein: Guanine nucleotide binding protein
Extracellular fluid
Intracellular fluid
Ligand(Agonist)
ReseptorConform. change
αβ γ
GDP
αβ γ
GTP
G-protein
GDP
GTP
Target
β γ
α
GTP
α
GDP+ P
Responce
HN
N N
N
O
OOP
O
O
OP
O
O
O
OHHO
n=1; GDPn=2; GTP
n
H2N
Subtypes of G-proteins - Targets (Second messenger systems)
Ion chanels: G12 Na+ / H+ exchange
Enzyms: Gi Inhib. Adenylyl cyclaseGs Stimul. Adenylyl cyclaseGq Stimul. 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
O
P OO
O
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 cyclaseGs Stimul. Adenylyl cyclaseGq Stimul. Phospholipase C
second messenger pathways
Phopholipase C
OO
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)
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 STAT
2) Release of STAT in cytoplasma3) STATto cell nucleus4) Intitation of transcription
STAT: Signal transducers and activators of transcription
Ligands: Peptide hormones
Cytoplasmic receptors
(not bound to cell membranes)
DNA
DNA mRNA
Protein
ResponceHSP-90
Cell membrane
Cytoplasma
Lipophil. ligand thru cell membrane
HSP-90
Cell nucleus
(HSP-90: Heat shock protein)
Receptor subtypesMost receptor classes - several sub-typesEach subtypes - differend A(nta)gonists
Sub types cholinerge reseptors
Nicotinergereceptors
Muscarinergereceptors
OH
N
NHO
H
O
HO
N
CNS
Effektor celle
Reseptor
Synapse
Acetylkolin
Noradrenalin
Det somatiske nervesystem Det autonome nervesystem
CNS CNS
Det sympatiskenervesystem
Det parasympatiskenervesystem
ganglion
4.3 Å
5.9 Å
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 chanelsIncr. Na+/Ca2+
NO
O
OH
ca. 5Å
Acetylcholin (Neurotransmittor)
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
Desensitizing
Sensitizing
Receptor and normal amount of ligand = agonist
Overstimulated receptor
Receptor and normal amount of ligand = Antagonist
Overstimulated receptor
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