1. Pharmacology-1 PHL 313 Fifth Lecture By Abdelkader Ashour, Ph.D. Phone: 4677212Email: aeashour@ksu.edu.sa

2. 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

3. 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 H 2 receptor has constitutive activity, which can be inhibited by the inverse agonist cimetidine. On the other hand, burimamide acts as a neutral antagonist

4. 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

5. 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

6. 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

7. 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

8. 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 β 2 receptors (lungs) rather than at β 1 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)

9. 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 = TD 50 /ED 50 or LD 50 /ED 50 where TD 50 is the dose that produces a toxic effect in 50% of the population, LD 50 is the dose that is lethal in 50% of the population and ED 50 is the dose that produces therapeutic response in 50% of the population  In general, a larger T.I. indicates a clinically safer drug TD 50

10. Therapeutic Index, contd. Why don’t we use a drug with a T.I. <1? Why don’t we use a drug with a T.I. <1? ED 50 > TD 50 = Very Bad!

11. 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.

12. 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