Dr.

Mahwish Akhtar
Ph.D. (Pharm. Chem.)
Assistant Professor
DCOP, DUHS

MEDICINAL CHEMISTRY I
617
Lecture 5
4th year, 7th semester
 OBJECTIVES
• At the end of lecture student will be able to
• Receptors
• History
• Role of chemical bonding
• Types of receptor
• Theories of receptor
RECEPTORS & DRUG ACTION

Chapter 7
Page # 263
 RECEPTORS & DRUG ACTION

• Ligands
• 5HT
• Epi or nor-epinephrine
• Dopamine
• Histamine
• Receptor
• Orphan receptor
• Orphan drugs ---- neurofibromatosis
• MAGIC BULLET
 RECEPTORS & DRUG ACTION

• HISTORICAL PERSPECTIVES
• LOOK & KEY
 RECEPTORS & DRUG ACTION

• HISTORICAL PERSPECTIVES
• SPECIFIC RECEPTORS
• NON SPECIFIC RECEPTOR
– Osmotic diuretics
– Anti-neoplastic drugs (mechlorethamine)
– Nitrogen mustard
– Antacids
RECEPTORS & DRUG ACTION
 RECEPTORS & DRUG ACTION

• Agonist
– Full agonist
– Partial agonist
• Antagonist
• Inverse agonist
RECEPTORS & DRUG ACTION
RECEPTORS & DRUG ACTION
TYPES OF RECEPTORS
TYPES OF RECEPTORS
 Ligand-gated ion channels (ionotropic
receptor)
• Ligand-gated ion channels (ionotropic receptor)
– Membrane protein similar to other ion channels
– Fast neurotransmitters
– Ions (Na+, K+, Ca+, Cl-)
• Examples
– Nicotinic acetylcholine receptor
– GABAA receptor
– Glutamate receptor
– N-methyl-D- aspartic acid
Ligand-gated ion channels (ionotropic
receptor)
 G-protein-coupled receptors
(metabotropic)
• G-protein-coupled receptors (metabotropic)
– Usually are cyclic adenosine monophosphate
(cAMP) and inositol triphosphate (IP3)
• Examples
– Muscarnic receptor
– Beta adrenergic receptor
– Serotonin receptor
– Opioid receptor
G-protein-coupled receptors
(metabotropic)
 Kinase-linked receptors

• Kinase-linked receptors
– Consist of extracellular ligand-binding domain that is
linked to an intracellular (IC) domain by single trans-
membrane helix.
– IC enzymatic in nature
– Receptor subunit bind to enzyme called Janus-Kinase.
• Examples
– Insulin
– Cytokinase
Kinase-linked receptors
 Nuclear receptors
• Nuclear receptors
– NR regulate the gene transcriptions, are located
in the cytosol, and migrate to the nuclear
compartment when a ligand is present
– The receptor protein is inherently capable of
binding to specific gene
• Examples
– Glucocorticoids
– Thyroid hormone
Nuclear receptors
TYPES OF RECEPTORS
 AFFINITY
ROLE OF CHEMICAL BONDING
 AFFINITY
ROLE OF CHEMICAL BONDING
 COVALENT BOND
• Covalent Bond
• Strength (50-150kcal/mol)
• Irreversible
 COVALENT BOND
• IRREVERSIBLE α–BLOCKERS
• α-adrenoceptor via
phenoxybenzamine
– Phenoxybenzamine –
carbonium ion (IM
haloalkylamine)—alkylation
with amino, sulfhydryl or
carboxyl gp of receptor
• Used only to relieve the
sympathetic effects of
pheochromocytoma.
COVALENT BOND
PAIN PREVENTER Pfizer’s PF-04457845
forms a covalent bond with fatty acid
amide hydrolase. The company completed
a Phase II clinical trial for pain but
stopped developing the compound last
year.

TUMOR TERMINATOR Pharmacyclics’

PCI-32765 forms a covalent bond with
Bruton’s tyrosine kinase. It is in Phase II
clinical trials for B-cell cancers.
COVALENT BOND
 IONIC BOND
• Ionic Bond
• Strength (5-10kcal/mol)
• N-acetylcholine with carboxyl group
– Hydrogen (2.1 LPU)
– Halide
– Hydroxyl
– Sulfhydryl
– Carboxyl
– Alkyl (not form ionic bond)
 IONIC BOND
• N-acetylcholine with carboxyl group
 HYDROGEN BOND

• Hydrogen Bond
• Strength (2-5kcal/mol)
HYDROGEN BOND
 HYDROPHOBIC BOND

• Hydrophobic Bond
• Strength (0.5-1kcal/mol)
• Nonpolar molecule
 HYDROPHOBIC BOND

Receptor binding of acetylcholine

HYDROPHOBIC BOND
 DIPOLE INTERACTION

• Dipole-Dipole
 DIPOLE INTERACTION

• Ion-Dipole Interactions
 DIPOLE INTERACTION

• Dipole-Dipole & Ion-Dipole Interactions

 VANDER WAALS FORCE

• Vander Waals forces

• Nonpolar compound
• Nonsymmetrical
distribution
• Temporary dipole
• Intermolecular
attraction
VANDER WAAL’S FORCE

Receptor binding of Phenylethanolamine

 CHARGE TRANSFER COMPLEX

Charge transfer complex

(30 kj/mol)

• e- donating group
– Furan • e- accepting group
– Thiophene – Purines
– Aromatics with e- donar – Pyrimidines
gp – Aromatics with e-
– Nonbonding e- pair acceptor gp
RECEPTOR BINDING
TYPES OF BONDING
Agonist and antagonist
 AFFINITY
THE ROLE OF CONFORMATION

THEORIES OF RECEPTORS
 RECEPTORS THEORIES

OCCUPATION THEORY

RATE THEORY

INDUCED FIT THEORY

MACROMOLECULAR PERTURBATION THEORY

ACTIVATION-AGGREGATION THEORY
 Occupation Theory

• OCCUPATION THEORY
– Intensity of effect is directly proportional to the
no. of receptors occupied by drug.
• Depends on
– Amount of dose
– Total no. of receptors
– Intrinsic activity
 Rate Theory

• RATE THEORY
– No. of drug receptor interaction per unit time
– Rate of association and dissociation of drugs
– It is not the function of no. occupied receptors

Effect
 Induced Fit Theory
• INDUCED FIT THEORY
– Receptor does not exist in proper conformation for
binding
– Drug approaches the receptor, a conformational
change occur in receptor to allow effective binding.
• Examples
– Acetylcholine interacts with the regulating protein &
alters normal forces that stabilizes structure of
protein, producing rearrangement in membrane
structure, change ion regulating property
Induced Fit Theory
Induced Fit Theory
 Macromolecular Perturbation Theory
• MACROMOLECULAR PERTURBATION THEORY
– Specific conformational perturbations (SCPs)
• Agonist
– Non-Specific conformational perturbations (NSCPs)
• Antagonist
• Examples
• Alkyl trimethyl ammonium ions
– C1 to C6--- alter receptor structure & produces
muscarinic agonistic action
– C7 ---- Partial Agonist
– C8 to C12------ Antagonist
 Activation-Aggregation Theory
• ACTIVATION-AGGREGATION THEORY
– Receptor is in a state of dynamic equilibrium b/
w an activated form & inactive form
– Agonist shift equilibrium toward activation
– Antagonist shift equilibrium toward inactivation

Antagonist
RESTING ACTIVE
Agonist
 Activation-Aggregation Theory
Two-state (Multi-state) Receptor Model
• R and R* are in equilibrium (equilibrium constant L),
which defines the basal activity of the receptor.
• In the multi-state model there is more than one R
state to account for variable agonist and inverse
agonist behavior for the same receptor type.
 Activation-Aggregation Theory
• Antagonists have equal
affinities for both R and R*
• Full inverse (no effect on basal activity) • Full agonists
agonists bind bind only to R*
only to R • Partial agonists
• Partial inverse bind
agonists bind preferentially to
preferentially R*
to R
Tx-Low heart rate

Tx-High BP

Tx - High BP
 REFERENCES
• Foye’s the Principles of Medicinal Chemistry, 6th ed,
Lippincott William & Wilkins
• Textbook of medicinal chemistry, Vol 1, by V.
Alagarsamy, Elsevier.