Download 5th Lecture 1433

Pharmacology-1 PHL 313
Fifth Lecture
By
Abdelkader Ashour, Ph.D.
Phone: 4677212
Email: [email protected]
Drug Receptor Interactions,
The two-state model of receptor activation
 The receptor is in two conformational states, ‘resting’ (R) and ‘active’ (R*), which exist in
equilibrium
 Normally, when no ligand is present, the equilibrium lies far to the left, and a few receptors are
found in the R* state
 For constitutively active receptors, an appreciable proportion of receptors adopt the R*
conformation in the absence of any ligand
 Agonists have higher affinity for R* than for R and thus shift the equilibrium from the resting
state (R) to the active (R*) state and hence, produce a response
(Activated state)
(Resting state)
(Active state)
Drug Receptor Interactions, Inverse agonist
 Inverse agonist
“An agent which binds to the same receptor
binding-site as an agonist for that receptor but
exerts the opposite pharmacological effect”
 Difference from Antagonist: Antagonist binds to the
receptor, but does not reduce basal activity
 Agonist  positive efficacy
 Antagonist  zero efficacy
 Inverse agonist  negative efficacy
 Inverse agonists are effective against certain types
of receptors (e.g. certain histamine receptors and
GABA receptors) which have constitutive activity
 Example 1: The agonist action of benzodiazepines on the benzodiazepine
receptor in the CNS produces sedation, muscle relaxation, and controls
convulsions. b-carbolines (inverse agonists) which also bind to the same receptor
cause stimulation, anxiety, increased muscle tone and convulsions
 Example 2: The histamine H2 receptor has constitutive activity, which can be
inhibited by the inverse agonist cimetidine. On the other hand, burimamide acts
as a neutral antagonist
Drug Receptor Interactions,
The two-state model of receptor activation & Inverse Agonist
 An inverse agonist has higher affinity for R than for R* and thus will shift the
equilibrium from the active (R*) to resting state (R) state
 A neutral antagonist has equal affinity for R and R* so does not by itself affect the
conformational equilibrium but reduces by competition the binding of other
ligands
 In the presence of an agonist, partial agonist or inverse agonist, the
antagonist restores the system towards the constitutive level of activity
Inverse Agonist
Antagonist
(Activated state)
(Resting state)
(Active state)
Drug Receptor Interactions,
The two-state model of receptor activation & Inverse Agonist, contd.
 An inverse agonist has higher affinity for R than for R* and thus will shift the
equilibrium from the active (R*) to resting state (R) state
 A neutral antagonist has equal affinity for R and R* so does not by itself affect the
conformational equilibrium but reduces by competition the binding of other
ligands
 In the presence of an agonist, partial agonist or inverse agonist, the
antagonist restores the system towards the constitutive level of activity
Drug-Receptor Bonds
1. Covalent Bond
-Very strong
-Not reversible under biologic conditions 
unusual in therapeutic drugs
Example: Phenoxybenzamine at a adrenergic
receptors
The rest of pharmacology is concerned with
weak, reversible, electrostatic attractions:
2. Ionic bond
-Weak, electrostatic attraction between positive
and negative forces
-Easily made and destroyed
3. Dipole - dipole interaction
-A stronger form of dispersion forces formed by the
instantaneous dipole formed as a result of
electrons being biased towards a particular atom
in a molecule (an electronegative atom).
-Example: Hydrogen bonds
Drug-Receptor Bonds,
4. Hydrophobic interactions
“The tendency of hydrocarbons (or of lipophilic
hydrocarbon-like groups in solutes) to form
intermolecular aggregates or intramolecular
interactions in an aqueous medium”
-usually quite weak
-Important in the interactions of highly lipidsoluble drugs with the lipids of cell membranes
and perhaps in the interaction of drugs with the
internal walls of receptor “pockets”
5. Dispersion (Van der Waal) forces
-Attractive forces that arise between particles as
a result of momentary imbalances in the
distribution of electrons in the particles
-These imbalances produce fluctuating dipoles
that can induce similar dipoles in nearby
particles, generating a net attractive force
contd.
Drug-Receptor Bonds and Selectivity
 Drugs which bind through weak bonds to their receptors are generally more
selective than drugs which bind through very strong bonds
 This is because weak bonds require a very precise fit of the drug to its
receptor if an interaction is to occur
 Only a few receptor types are likely to provide such a precise fit for a
particular drug structure
 To design a highly selective short acting drug for a particular receptor, we
would avoid highly reactive molecules that form covalent bonds and instead
choose molecules that form weaker bonds
 Selectivity:
Preferential binding to a certain receptor subtype leads to a greater effect at
that subtype than others
-e.g. salbutamol binds at β2 receptors (lungs) rather than at β1 receptors
(heart)
 Lack of selectivity can lead to unwanted drug effects.
-e.g. salbutamol (b2-selective agonist ) vs isoprenaline (non-specific b-agonist) for
patients with asthma. Isoprenaline  more cardiac side effects (e.g.,
tachycardia)
Therapeutic Index (T.I.)
 A measure of drug safety
 The ratio of the dose that produces toxicity to the dose that produces a clinically
desired or effective response in a population of individuals
 Therapeutic Index = TD50/ED50 or LD50/ED50
where TD50 is the dose that produces a toxic effect in 50% of the population, LD50 is
the dose that is lethal in 50% of the population and ED50 is the dose that produces
therapeutic response in 50% of the population
 In general, a larger T.I. indicates a clinically safer drug
TD50
Therapeutic Index, contd.
Why don’t we use a
drug with a T.I. <1?
ED50 > TD50 = Very Bad!
Therapeutic Index (T.I.),
• High therapeutic index
– NSAIDs
• Aspirin
• Tylenol
• Ibuprofen
– Most antibiotics
– Beta-blockers
contd.
• Low therapeutic index
– Lithium
– Neuroleptics
• Phenytoin
• Phenobarbital
– Digoxin
– Immunosuppressives
Spare Receptors
 In some systems, full agonists are capable of eliciting 50% response with
less than 50% of the receptors bound (receptor occupancy)
 Maximal effect does not require occupation of all receptors by agonist
 Low concentrations of competitive irreversible antagonists may bind to
receptors and a maximal response can still be achieved
 Pool of available receptors exceeds the number required for a full response
 Common for receptors that bind hormones and neurotransmitters
 if [R] is increased, the same [DR] can be achieved with a smaller [D]
 A similar physiological response is achieved with a smaller [D]
 Economy of hormone or neurotransmitter secretion is achieved at the
expense of providing more receptors