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

Cell 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

Nu

N

Cl

Nu

Drugs that do act on receptors:

NO

O

OH

ca. 5Å

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

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

NO

O

Acetylkolin(AcCh)

Acetylkolin-esterase

Kolin Acyltransferase

NOH

Kolin(Ch)

Reversible inhibitors

OH OO

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 ON

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 OP

OH

L

OR

R1O

HO

PO

OR

R1

Aging

OP

OH

R1O

Pralidoxim

N

N

OH

Me

OH

Pralidoxim

motgift

N

N

O

Me

P

OOR

R1

Gen structur mustard gasses

PO

O

N

N

Tabun

FPO

O

Sarin

LPO

R1

R2

L: Leaving groupR1: alkoksyR2: alkyl, alkoksy, amino

O

O

O

O

SPS

O

O

Malation

only insects

O

O

O

O

SPO

O

O

Malaoxon

Act as mustard gassesnot tox.

Ionic bond

5-10 kcal/mol,

Reversible bonding

NO

O

OH

Acetylcholin

Hydrogen bond

2-5 kcal/mol,

Reversible bonding

NO

O

OH

Hydrophobic interaction

0.5-1 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 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

Ligand gated ion chanels

Fastest intracellular responce, µs

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

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

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

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 cyclase

Gs Stimul. Adenylyl cyclase

Gq Stimul. Phospholipase C

second messenger pathways

Phopholipase C

O

O

HOHO

OOH

P

P

PO

O

O

O

O

O

R'

O

R

PIP2

Phosphatidylinositol besphophate

O

O

HOHO

OOH

P

P

P

OH

O

O

O

O

O

R'

O

R

O

+

IP3

Inositol-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 PSTATSprotein 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

DNAmRNA

Protein

Responce

HSP-90

Cell membrane

Cytoplasma

Lipophil. ligand thru cell membrane

HSP-90

Cell nucleus

(HSP-90: Heat shock protein)

Receptor subtypes

Most receptor classes - several sub-types

Each subtypes - differend A(nta)gonists

Sub types cholinerge reseptors

Nicotinerge

receptors

Muscarinerge

receptors

OH

N

N

HOH

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 chanels

Incr. Na+/Ca2+

Nneuro: Ligand gated ion chanels

Incr. 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