Drug Chemistry and Toxicology

CHE 618

Alexander Nazarenko

The Receptor Concept

The Nature of Drug Receptors

Drug Parameters: Affinity and Efficacy

The Langmuir Isotherm equation

Opioid receptor

Insulin receptor

Transmembrane receptor

Occupation theoryDrug effect is directly proportional to number of receptors occupied Drug effect ceases as drug-receptor complex dissociateAriens & Stephenson theory introduced terms of "affinity" & "efficacy" Affinity: ability of the drug to combine with receptor to create drug-receptor complex Efficacy: ability of the drug-receptor complex to initiate a responseAffinity “drug-receptor interaction” is governed by the law of mass action.In this theoryAgonist: drug with high affinity & high intrinsic activity Partial agonist: drug with high affinity & low intrinsic activityAntagonist: drug with high affinity & low intrinsic activityRate theoryThe activation of receptors is directly proportional to the total number of encounters of the drug with its receptors per unit time Pharmacological activity is directly proportional to the rate of dissociation & association not number of receptors occupiedAgonist: drug with fast association & fast dissociation Partial agonist: drug with intermediate association & intermediate dissociation Antagonist: drug with fast association & slow dissociationInduced fit theoryAs the drug approaches the receptor the receptors alters the conformation of its binding site to produce drug—receptor complex

From the Greek αγωνιστής (agōnistēs), contestant; champion; rival < αγων (agōn), contest, combat; exertion, struggle < αγω (agō), I lead, lead towards, conduct; drive

An agonist is a chemical that binds to a receptor and triggers a response. Whereas an agonist causes an action, an antagonist blocks the action of the agonist and an inverse agonist causes an action opposite to that of the agonist.

Drug + Receptor [Drug/Receptor Complex]

ActionK

0

0.2

0.4

0.6

0.8

1

0.0001 0.001 0.01 0.1 1

0

0.2

0.4

0.6

0.8

1

0 0.005 0.01 0.015 0.02 0.025

0

0.2

0.4

0.6

0.8

1

0 0.05 0.1 0.15 0.2

CK

C

C

C

1

β = 100 K = 1/100 = 0.01

The Langmuir Isotherm

0

0.2

0.4

0.6

0.8

1

0 0.005 0.01 0.015 0.02 0.025

1/a

1/C

a

C

C/a

C

Various plots

Lineweaver–Burk plot

Hanes–Woolf plot

Lineweaver–Burk or double-reciprocal plot of kinetic data, showing the significance of the axis intercepts and gradient.

Michaelis-Menten Plot relating the reaction rate V to the substrate concentration [S].

V Vmax S K S

Michaelis–Menten kinetics

Agonists

Partial Agonist

AntagonistAntagonists bind to receptors but do not activate them. This results in receptor blockage, inhibiting the binding of other agonists.

Inverse Agonist

Partial agonists do not activate receptors thoroughly, causing responses which are partial compared to those of full agonists

Full agonists are able to activate the receptor and result in a maximal biological response.

Inverse agonists reduce the activity of receptors by inhibiting their constitutive activity.

+1

0

-1

Fun

ctio

nal R

espo

nse

Log[Drug]

Full Agonist

Partial Agonist

Neutral Antagonist

Full Inverse Agonist

Competitive Antagonism

A1 + Receptor {A1 Receptor} effect

A2 + Receptor {A2 Receptor}

][2][1

][

21

1

AA

A

R

A1 A2

RA1

RA2

RA1

A2

][][][2][1

][

211221

1

AAAA

A

][][][2][1

][][

211221

2112

AAAA

AA

Receptor-A1 is active

Receptor-A1-A2 is active

Similar:

In coordination chemistry Metal Ion + Ligand 1 + Ligand 2

In enzyme kinetics Enzyme + Substrate + Inhibitor

Dose-response curve

What is there that is not poison?All things are poison and nothing without poisonSolely the dose determines that a thing is not a poison