This document discusses theories of drug receptor interaction. It describes the occupation theory which states that pharmacological effect is proportional to the number of occupied receptors. It also discusses the rate theory, induced fit theory, macromolecular perturbation theory, activation-aggregation theory, and two-state model of receptor activation. Each theory provides a different perspective on how drugs interact with receptors and elicit biological responses.

1. THEORIES OF DRUG
INTERACTION
PRESENTED BY – TATHAGATA PRADHAN
1st YEAR M. PHARM
DEPT. OF PHARMACEUTICAL CHEMISTRY

2. DRUG
• It is a natural or synthetic substances which has a physiological effects
when administered into the body.
RECEPTOR
• It is a specific binding site present on the cell surface made up of
protein or nucleic acid where a ligand can bind and initiates a
characteristic response.

3. TYPES OF RECEPTORS
• Intracellular Receptors
• Cellular Receptors :-
1. Ligand-gated ion channels
2. G protein-coupled receptors
3. Tyrosine kinases receptors

4. Intracellular receptors
Intracellular receptors are receptor proteins found on the inside of the cell,
typically in the cytoplasm or nucleus. In most cases, the ligands of
intracellular receptors are small, hydrophobic (water-hating) molecules,
since they must be able to cross the plasma membrane in order to reach
their receptors. For example, the primary receptors for hydrophobic steroid
hormones, such as the sex hormones estradiol (an estrogen) and
testosterone, are intracellular.
When a hormone enters a cell and binds to its receptor, it causes the
receptor to change shape, allowing the receptor-hormone complex to
enter the nucleus (if it wasn’t there already) and regulate gene activity.
Hormone binding exposes regions of the receptor that have DNA-binding
activity, meaning they can attach to specific sequences of DNA. These
sequences are found next to certain genes in the DNA of the cell, and when
the receptor binds next to these genes, it alters their level of transcription.

6. Cell-surface receptors
Cell-surface receptors are membrane-anchored proteins that bind to
ligands on the outside surface of the cell. In this type of signaling, the
ligand does not need to cross the plasma membrane. So, many
different kinds of molecules (including large, hydrophilic or "water-
loving" ones) may act as ligands.
A typical cell-surface receptor has three different domains, or protein
regions: a extracellular ("outside of cell") ligand-binding domain, a
hydrophobic domain extending through the membrane, and an
intracellular ("inside of cell") domain, which often transmits a signal.
The size and structure of these regions can vary a lot depending on
the type of receptor, and the hydrophobic region may consist of
multiple stretches of amino acids that criss-cross the membrane.

7. There are many kinds of cell-surface receptors, but here we’ll look at
three common types:
• Ligand-gated ion channels
• G protein-coupled receptors
• Tyrosine kinases receptors

8. Ligand-gated ion channels
Ligand-gated ion channels are ion channels that can open in response to the
binding of a ligand. To form a channel, this type of cell-surface receptor has
a membrane-spanning region with a hydrophilic (water-loving) channel
through the middle of it. The channel lets ions to cross the membrane
without having to touch the hydrophobic core of the phospholipid bilayer.
When a ligand binds to the extracellular region of the channel, the protein’s
structure changes in such a way that ions of a particular type, such as Ca2+
or Cl-1 , can pass through. In some cases, the reverse is actually true: the
channel is usually open, and ligand binding causes it to close. Changes in
ion levels inside the cell can change the activity of other molecules, such as
ion-binding enzymes and voltage-sensitive channels, to produce a
response. Neurons, or nerve cells, have ligand-gated channels that are
bound by neurotransmitters.

10. G protein-coupled receptors
GPCRs interact with G proteins in the plasma membrane. When an
external signaling molecule binds to a GPCR, it causes a conformational
change in the GPCR. This change then triggers the interaction between
the GPCR and a nearby G protein.
G proteins are specialized proteins with the ability to bind the
nucleotides guanosine triphosphate (GTP) and guanosine diphosphate
(GDP). Some G proteins, such as the signaling protein Ras, are small
proteins with a single subunit. However, the G proteins that associate
with GPCRs are heterotrimeric, meaning they have three different
subunits: an alpha subunit, a beta subunit, and a gamma subunit. Two
of these subunits — alpha and gamma — are attached to the plasma
membrane by lipid anchors .

11. • A G protein alpha subunit binds either GTP or GDP depending on whether
the protein is active (GTP) or inactive (GDP). In the absence of a signal, GDP
attaches to the alpha subunit, and the entire G protein-GDP complex binds
to a nearby GPCR. This arrangement persists until a signaling molecule
joins with the GPCR. At this point, a change in the conformation of the
GPCR activates the G protein, and GTP physically replaces the GDP bound
to the alpha subunit. As a result, the G protein subunits dissociate into two
parts: the GTP-bound alpha subunit and a beta-gamma dimer. Both parts
remain anchored to the plasma membrane, but they are no longer bound
to the GPCR, so they can now diffuse laterally to interact with other
membrane proteins. G proteins remain active as long as their alpha
subunits are joined with GTP. However, when this GTP is hydrolyzed back to
GDP, the subunits once again assume the form of an inactive heterotrimer,
and the entire G protein reassociates with the now-inactive GPCR. In this
way, G proteins work like a switch — turned on or off by signal-receptor
interactions on the cell's surface.

13. Receptor tyrosine kinases
Enzyme-linked receptors are cell-surface receptors with intracellular
domains that are associated with an enzyme. In some cases, the intracellular
domain of the receptor actually is an enzyme that can catalyze a reaction.
Other enzyme-linked receptors have an intracellular domain that interacts
with an enzyme.
Receptor tyrosine kinases (RTKs) are a class of enzyme-linked receptors
found in humans and many other species. A kinase is just a name for an
enzyme that transfers phosphate groups to a protein or other target, and a
receptor tyrosine kinase transfers phosphate groups specifically to the amino
acid tyrosine.
How does RTK signaling work?
In a typical example, signaling molecules first bind to the extracellular
domains of two nearby receptor tyrosine kinases. The two neighboring
receptors then come together, or dimerize. The receptors then attach
phosphates to tyrosines in each others' intracellular domains. The
phosphorylated tyrosine can transmit the signal to other molecules in the
cell.

16. Classification of ligands
Ligands are classified by effects upon binding to receptors

20. THEORIES OF DRUG RECEPTORS INTERACTION
1. Occupation theory
2. Rate Theory
3. The induced-fit theory of enzyme-substrate interaction
4. Macromolecular perturbation theory
5. Activation-aggregation theory
6. Two state model of receptor activation

21. OCCUPATION THEORY
• This theory was given by Gaddum and Clark
• This theory states that the intensity of pharmacological effect is directly proportional to the number of receptors that are occupied
by the drug
• Drugs act on binding sites and activate them, resulting in a biological response that is proportional to the amount of drug-receptor
complex formed.
• The response ceases when this complex dissociates.
• Intensity of pharmacological effect is directly proportional to number of receptors occupied
D + R DR RESPONSE
• Response is proportional to the fraction of occupied receptors
• Maximal response occurs when all the receptors are occupied
• This theory was not acceptable for partial agonist. Hence Arieus and Stephenson modify occupancy theory to account for partial
agonist.
• Their concept was based on involvement of two stage during drug receptor interaction
1. There is complexation of drug with receptor known as Affinity.
2. There is initiation of biological effect which Arieus called it as Intrinsic activity whereas Stephanson called it as Efficiency

22. • Affinity - It is the measure of capacity of drug to bind to receptors
dependent on molecular complementarily of drug and receptor.
• Intrinsic activity – It is defined as maximum response induced bya
compound relative to a reference compound.
• Efficacy – It the property of compound that produces the maximum
response or ability of drug – receptor complex.

23. Rate Theory
• This theory is given by Paton
• Activation of receptors is proportional to the total number of
encounters of a drug with its receptor per unit time.
• Therefore this theory suggests that activity is a function of rate of
association and dissociation of drug with receptor and not the
number of occupied receptor.
• According to this view, the duration of Receptor occupation
determines whether a molecule is agonist, partial agonist.

24. Induced-Fit Theory of enzyme substrate reaction
• This theory was given by Koshland
• Theory was originally proposed for action of substrates and enzymes
but could not apply to drug – receptor interaction
• According to this theory, Receptors need not necessarily exist in
appropriate conformation required to bind the drug.
• As the drug approaches the receptor , a conformational change in
receptor could be responsible for initiation of biological response.
• Receptor was suggested to be elastic and it could return to its original
conformation after the drug product was released.

25. • According to this theory ,
1. Agonist would induce conformational change in response
2. Antagonist would bind without a conformational change
3. Partial agonist will induce partial conformational change
4. Other theories evolved from induced-fit theory, such as
macromolecular perturbation theory, activation aggregation theory
and multistage models.

26. Macromolecular Perturbation Theory
• This theory was given by Bellean
• During the interaction of drug with receptor there are two general
types of macromolecular perturbations could result as following:
1. Specific Conformational perturbations which makes possible the
binding of agonist.
2. Non-Specific Conformational perturbation which accommodates
other types of molecules that do not elicit response.

27. Activation – Aggregation Theory
• This theory was given by Monad, Wyman and Changuix and Karlin
• This theory is extension of macromolecular perturbation theory.
• According to which even in absence of drugs receptor is in a state of
dynamic equilibrium between Rₒ and Tₒ
where Rₒ is Activated form
Tₒ is Inactive form
Agonist bind to Rₒ and shift the equilibrium to the activated form
whereas antagonist bind to inactive form Tₒ and partial agonist bind
to both.

28. Two-State (Multi-state) Receptor Model
• R and R* are in equilibrium (equilibrium constant L), which defines the
basal activity of the receptor.
• Full agonists bind only to R*
• Partial agonists bind preferentially to R*
• Full inverse agonists bind only to R
• Partial inverse agonists bind preferentially to R