Drug Receptors

1. Drug Receptors Lakshman Karalliedde October 2011

2. DRUG RECEPTORS A RECEPTOR IS THE SPECIFIC CHEMICAL CONSTITUENT OF THE CELL WITH WHICH A DRUG INTERACTS TO PRODUCE IT’S PHARMACOLOGICAL EFFECTS. Some receptor sites have been identified with specific parts of proteins and nucleic acids. In most cases, the chemical nature of the receptor site remains obscure.

3. Receptor : Any cellular macromolecule that a drug binds to initiate its effects. Drug : A chemical substance that interacts with a biological system to produce a physiologic effect. All drugs are chemicals but not all chemicals are drugs. The ability to bind to a receptor is mediated by the chemical structure of the drug that allows it to Interact with complementary surfaces on the receptor. Once bound to the receptor an agonist activates or enhances cellular activity. Examples of agonist action are drugs that bind to beta receptors in the heart and increase the force of myocardia contraction or drugs that bind to alpha receptors on blood vessels to increase blood pressure. The binding of the agonist often triggers a series of biochemical events that ultimately leads to the alteration in function.

4. HOW DRUGS ACT l. Enzyme Inhibition: Drugs act within the cell by modifying normal biochemical reactions. Enzyme inhibition may be reversible or non reversible; competitive or non-competitive. Antimetabolites may be used which mimic natural metabolites. Gene functions may be suppressed. 2. Drug-Receptor Interaction: Drugs act on the cell membrane by physical and/or chemical interactions- usually through specific drug receptor sites known to be located on the membrane. Some receptor sites have been identified with specific parts of proteins and nucleic acids. In most cases, the chemical nature of the receptor site remains obscure. 3. Non-specific Interactions: Drugs act exclusively by physical means outside of cells. These sites include external surfaces of skin and gastro-intestinal tract. Drugs also act outside of cell membranes by chemical interactions. Neutralization of stomach acid by antacids is a good example

5. Dose-Response Curves Dose-response relationships are a common way to portray data in both basic and clinical science. For example, a clinical study may examine the effect of increasing amounts of an analgesic on pain threshold. To present the data, the concentration of the drug would be plotted on the x-axis and the effect on pain threshold would be presented on the y-axis. A plot of drug concentration ([D]) versus effect (E/Emax) (or for that matter DR/RT) is a rectangular hyperbola. Notice how the drug effect reaches a plateau or maximum. This is because there are a finite number of receptors. Hence, the response must eventually reach a maximum. However, the hyperbolic plot is a cumbersome graph because drug concentrations often vary over 100 to 1000-fold. This necessitates a long X-axis. To overcome this problem, the log of the drug concentration is plotted versus the effect. A plot of the log of [D] versus E/Emax is a sigmoid curve.

6. As illustrated below, the position and shape of the log-dose response curve is dependent on the affinity of the ligand for the receptor and its intrinsic activity. Affinity determines the position of the dose-response curve on the X-axis, while intrinsic activity affects the magnitude of the response.

7. In most physiological systems in which drugs will be administered, the relationship between receptor occupancy and response is not linear but some unknown function f of receptor occupancy. In the graph, this unknown function is presented as being hyperbolic. As the graph depicts in this type of system, all receptors do not have to be occupied to produce a full response. Because of this hyperbolic relationship between occupancy and response, maximal responses are elicited at less than maximal receptor occupancy. A certain number of receptors are "spare." Spare receptors are receptors which exist in excess of those required to produce a full effect. There is nothing different about spare receptors. They are not hidden or in any way different from other receptors.

8. Norepinephrine and phenylephrine are full agonists with intrinsic activity values of 1. However, Norepinephrine has a higher affinity for the receptor. As is illustrated, affinity affects the position of the dose-response curve on the x-axis.

9. Factors Governing Drug Action Two factors that determine the effect of a drug on physiologic processes are 1. Affinity 2.Intrinsic activity. Affinity is a measure of the tightness that a drug binds to the receptor. Intrinsic activity is a measure of the ability of a drug once bound to the receptor to generate an effect activating stimulus and producing a change in cellular activity.

11. The binding of a drug to a receptor is determined by the following forces: Hydrogen bonds Ionic bonds Van der Waals forces Covalent bonds Understanding Affinity To bind to a receptor the functional group on a drug must interact with complementary surfaces on the receptor. The binding of a drug, illustrated here as D, to the receptor, illustrated as R, can be described by this expression.

13. Agonists initiate changes in second messengers. Once bound to the receptor an agonist activates or enhances cellular activity. Examples of agonist action are drugs that bind to beta receptors in the heart and increase the force of myocardial contraction or drugs that bind to alpha receptors on blood vessels to increase blood pressure. The binding of the agonist often triggers a series of biochemical events that ultimately leads to the alteration in function. The biochemicals that initiate these changes are referred to as second messengers. or antagonists. Antagonists have the ability to bind to the receptor but do not initiate a change in cellular function. Because they occupy the receptor, they can prevent the binding and the action of agonists. Hence the term antagonist. Antagonists are also referred to as blockers.

14. Affinity and intrinsic activity are independent properties of drugs. Agonists have both affinity - the ability to bind to the receptor as well as intrinsic activity-the ability to produce a measurable effect. Antagonists, on the other hand, only have affinity for the receptor. This property allows antagonists to bind to the receptor. However, because antagonists do not have intrinsic activity at the receptor no effect is produced. Because they are bound to the receptor, they can prevent binding of agonists. This is a diagram of a G-protein coupled receptor. Notice how the amino acids that make up the receptor protein can contribute functional groups to allow a drug to bind to this receptor.

16. This is a reversible reaction and when at equilibrium, the rate of drug-receptor complex formation [DR] is equal to the rate of drug-receptor complex dissociation. The rate of formation of the drug-receptor complex is described by k1. The rate at which the drug receptor complex dissociates is described by k-1. The binding of many, but not all, drugs to the receptor is a reversible process which reaches an equilibrium. The practical consequence of this is when binding is in equilibrium the amount of drug bound to the receptor is constant.

17. To summarize, the key features of a competitive antagonist are: • Reversible binding to the receptor. • The blockade can be overcome by increasing the agonist concentration. • The maximal response of the agonist is not decreased. • The agonist dose-response curve in the presence of a competitive antagonist is • displaced to the right parallel to the curve in the absence of agonist.

18. Antagonists Antagonists exhibit affinity for the receptor but do not have intrinsic activity at the receptor. An antagonist that binds to the receptor in a reversible mass-action manner is referred to as a competitive antagonist. Because the antagonist does not have intrinsic activity, once it binds to the receptor, it blocks binding of agonists to the receptor. A key point about competitive antagonists is that like agonists, they bind in a reversible manner. This has important implications regarding the effect competitive antagonists have on the configuration of the dose-response curve of agonists

19. Because competitive antagonists bind in a reversible manner, agonists, if given in high concentrations, can displace the antagonist from the receptor and the agonist can then produce its effect. The antagonist action can, in effect, be surmounted. Because the antagonist can be completely displaced, the agonist is still able to produce the same maximal effect observed prior to antagonist treatment. However, because higher agonist concentrations were necessary to displace the antagonist, the agonist dose-response curve is shifted to the right in the presence of a competitive antagonist. This can be illustrated with two equilibrium equations:

20. Irreversible Receptor Antagonists Another type of antagonist is referred to as an irreversible receptor antagonist. The properties of irreversible antagonists are markedly different from competitive antagonists. Irreversible receptor antagonists are chemically reactive compounds. These ligands first bind to the receptor. Following this binding step, the ligand then reacts with the functional groups of the receptor. The consequence of this chemical reaction is that the ligand becomes covalently bound to the receptor. Because a chemical bond is formed, an irreversible ligand does not freely dissociate from the receptor. It remains attached to the receptor for a long period of time. The synthesis of new receptor protein may be required to generate a receptor free of an irreversible blocker. Because the ligand is covalently bound to the receptor, the binding of agonists, and hence their pharmacologic activity, are blocked. Unlike competitive antagonists, the blocking activity of irreversible receptor antagonists can not be overcome by increasing the agonist concentration.

21. The antagonism therefore cannot be overcome by increasing the agonist concentration. Recall, that the effect of an agonist is proportional to the active drug-receptor complexes formed. Because an irreversible receptor antagonist reduces the total number of active receptors, [RT], the maximal pharmacologic effect Emax is also decreased. The reduction in maximal agonist reponse is the hallmark of irreversible antagonists. The shape of the dose-response curve is also altered because of this decrease in maximal effect. The dose-response is shifted to the right and the maximal response is depressed.

22. To summarize, the properties of irreversible receptor blockers are: • Chemically reactive compound, therefore covalently binds with the receptor • The receptor is irreversibly inactivated and the blockade can not be overcome with • increasing agonist concentration.. • 3. Shifts the agonist dose-response curve to the right and depresses maximal responsiveness.

23. Applications to Therapeutics Few drugs interact with one and only one receptor. Such a drug would be said to be specific, that is producing effects by specifically interacting with a single receptor. Most drugs interact with several receptors and thus have the capability to produce distinctly different pharmacologic effects. Some of these effects could be beneficial, some could be toxic. Such a drug would be said to be a selective. The factors that determine which particular effect of a drug will be observed are the affinity and intrinsic activity of a drug .