Pharmacology-1 PHL 313

Fifth Lecture

By

Abdelkader Ashour, Ph.D. Phone: 4677212 Email: aeashour@ksu.edu.sa

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

(Resting state)

(Active state)

(Activated state)Agonist

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. -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

Inverse Agonist Antagonist

(Resting state)

(Active state)

(Activated state)

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 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 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, contd.

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 lipid-soluble 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

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 (2-selective agonist ) vs isoprenaline (non-specific -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 adrug with a T.I. <1?

Why don’t we use adrug with a T.I. <1?

EDED5050 > TD > TD5050 = Very Bad! = Very Bad!EDED5050 > TD > TD5050 = Very Bad! = Very Bad!

• High therapeutic index– NSAIDs

• Aspirin• Tylenol• Ibuprofen

– Most antibiotics– Beta-blockers

• Low therapeutic index– Lithium– Neuroleptics

• Phenytoin• Phenobarbital

– Digoxin– Immunosuppressives

Therapeutic Index (T.I.), contd.

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