In biochemistry and pharmacology, a receptor is a protein molecule, usually embedded in the plasma membrane of the cell surface, that receives chemical signals from outside the cell. When such chemical signals bind to a receptor, they cause some form of cellular/tissue response, such as a change in the electrical activity of the cell. In this sense, a receptor is a protein molecule that recognizes and responds to endogenous chemical signals, for example, the acetylcholine receptor recognizes and responds to its endogenous ligand, acetylcholine. However, the term is sometimes also used in pharmacology for other proteins that are affected by drugs, such as enzymes, transporters, and ion channels. Receptor proteins are embedded in the plasma membranes of the cell; outside the cell (cell surface receptors), into the cytoplasm (cytoplasmic receptors), or into the nucleus (nuclear receptors). The molecule that binds to the receptor is called a ligand, and may be a peptide (short protein) or other small molecule such as a neurotransmitter, hormone, pharmaceutical drug, or toxin. The endogenously designated molecule for a particular receptor is called its endogenous ligand. For example, the endogenous ligand for the nicotinic acetylcholine receptor is acetylcholine, but the receptor can also be activated by nicotine and blocked by curare. Each receptor is associated with a specific cellular biochemical pathway. Despite the fact that most cells contain a huge number of different receptors, each receptor binds only to ligands of a specific structure, by analogy with a lock of a certain shape, to which only strictly defined keys fit. When a ligand binds to its corresponding receptor, it activates or inhibits the associated biochemical reactions of the receptor.
Structure
Receptor structures are very diverse and can generally be divided into the following categories:
Type 1: L (ionotropic receptors)
These receptors are typically targets for fast-acting neurotransmitters such as acetylcholine (nicotine) and GABA. Activation of these receptors leads to changes in the movement of ions across the membrane. These receptors have a hetero-structure. Each subunit consists of an extracellular ligand-binding domain and a transmembrane domain, and the transmembrane domain, in turn, includes four transmembrane alpha helices. Ligand binding cavities are located at the interface between subunits.
Type 2: G-protein coupled (metabotropic) receptors
This is the largest family of receptors, including receptors for a number of hormones and slow transmitters, for example, dopamine, metabotropic glutamate. These receptors are composed of seven transmembrane alpha helices. The loops connecting the alpha helices form the extracellular and intracellular domains. The binding sites for large peptide ligands are typically located in the extracellular domain, whereas the binding sites for small non-peptide ligands are often located between seven alpha helices and one extracellular loop. These receptors are coupled to various intracellular effector systems via G proteins.
Type 3: Kinase-related and related receptors
These receptors consist of an extracellular domain containing a ligand-binding region and an intracellular domain, often with enzymatic function, and are associated with a single transmembrane alpha helix, such as the insulin receptor.
Type 4: nuclear receptors
Despite their name, nuclear receptors are actually found in the cytosol and migrate into the nucleus after binding to their ligands. They consist of a C-terminal ligand-binding region, a nuclear DNA-binding domain, and an N-terminal domain that contains the AF1 (activation function 1) region. The nuclear region has two zinc extensions responsible for recognizing DNA sequences specific to a given receptor. The N-terminal interacts with other cellular transcription factors in a ligand-independent manner and, depending on these interactions, can alter receptor binding/activity. Examples of such receptors are steroid receptors and thyroid hormone receptors. Membrane receptors can be isolated from cell membranes as a result of complex extraction procedures using solvents, detergents and/or affinity purification methods. The structure and activity of the receptors can be studied using biophysical techniques such as X-ray crystallography, NMR, circular dichroism and dual polarization interferometry. Computer modeling methods of the dynamic behavior of receptors are used to better understand the mechanism of their action.
Binding and Activation
Ligand binding is an equilibrium process. Ligands bind to receptors and are repelled from them in accordance with the law of mass action. One measure of how well a molecule fits into a receptor is binding affinity, which is inversely related to the dissociation constant Kd. If a molecule fits well to a receptor, it has high affinity and low Kd. The final biological response (eg, secondary response cascade, muscle contraction) is achieved only after activation of a significant number of receptors. Affinity is a measure of the ease with which a ligand binds to a receptor. Efficacy is a measure of how a bound ligand activates a receptor.
Agonists vs. antagonists
Not every ligand that binds to a receptor can activate it. The following classes of ligands exist:
(Full) agonists are able to activate the receptor, causing a maximal biological response. The natural endogenous ligand that is most effective for a given receptor is, by definition, a full agonist (100% effective).
Partial agonists are unable to activate receptors with maximum efficiency, even at maximum binding, resulting in partial responses compared to full agonists (0 to 100% effective).
Antagonists bind to receptors but do not activate them. This leads to receptor blockade, inhibition of agonist and inverse agonist binding. Receptor antagonists may be competitive (or inverse) and compete with the agonist for the receptor, or they may be irreversible antagonists that form covalent bonds with the receptor and completely block it. An example of an irreversible antagonist is the protein pump inhibitor Omeprazole. The effects of irreversible antagonism can only be reversed by the synthesis of new receptors.
Inverse agonists reduce receptor activity by inhibiting their constitutive activity (negative efficacy).
Allosteric modulators: do not bind to the agonist binding site on the receptor, but instead bind to specific allosteric binding sites by which they modify the action of the agonist, for example benzodiazepines (BZDs) bind to benzodiazepine sites on GABA-A receptors and enhance the action of endogenous GABA.
Note that the idea of receptor agonism and antagonism only refers to the interactions between receptors and ligands, not their biological effects.
Constitutive activity of the receptor
A receptor that is able to carry out its biological response in the absence of a bound ligand exhibits so-called “constitutive activity.” The constitutive activity of the receptor can be blocked using an inverse agonist. The anti-obesity drugs Rimonabant and Tarannabant are inverse agonists of the cannabinoid receptor CB1 and, although both drugs were effective in reducing weight, they were withdrawn from the market due to high level incidence of depression and anxiety, which were presumably associated with inhibition of the constitutive activity of cannabinoid receptors. Mutations in receptors leading to increased constitutive activity underlie some hereditary diseases, such as precocious puberty (due to mutations in luteinizing hormone receptors) and hyperthyroidism (due to mutations in thyroid-stimulating hormone receptors).
Theories of drug-receptor interactions
Occupation theory
The central dogma of receptor pharmacology is that the effect of a drug is directly proportional to the number of receptors occupied. In addition, the effect of the drug ceases when the drug-receptor complex disintegrates. To describe the action of ligands bound to receptors, Arjens and Stevenson introduced the concepts of “affinity” and “efficacy”.
Affinity: the ability of a drug to bind to a receptor, creating a drug-receptor complex
Efficacy: the ability of the drug-receptor complex to initiate a reaction
Intensity theory
In contrast to the occupation theory, the intensity theory assumes that the rate of receptor activation is directly proportional to the total number of interactions of a drug with its receptors per unit time. Pharmacological activity is directly proportional to the rates of dissociation and association, and not to the number of occupied receptors:
Agonist: a drug with rapid association and rapid dissociation
Partial agonist: a drug with intermediate association and intermediate dissociation
Antagonist: drug with fast association and slow dissociation
Induced response theory
Once a drug finds a receptor, the receptor changes the conformation of its binding site, creating a drug-receptor complex.
Spare receptors
In some receptor systems, such as acetylcholine at the neuromuscular junction in smooth muscle, agonists are able to elicit maximal responses at very low levels of receptor occupancy (<1%). Таким образом, система имеет запасные рецепторы или резервные рецепторы. Это свойство обеспечивает экономичность производства и высвобождения нейромедиаторов.
Receptor regulation
Cells can increase (activate) or decrease (suppress) the number of receptors for a particular hormone or neurotransmitter, changing its sensitivity to that molecule. This represents a locally operating feedback mechanism.
A change in receptor conformation such that, for example, binding of an agonist does not activate the receptor. This can be seen with ion channel receptors.
Rejection of receptor effector molecules is observed with the G protein-coupled receptor.
Sequestration (internalization) of receptors, for example in the case of hormone receptors.
The role of receptors in the development of genetic disorders
Many genetic disorders are associated with inherited defects in receptor genes. It is often difficult to determine whether the cause of the disease is a dysfunctional receptor or insufficient levels of hormone production. These diseases are a “pseudo-hypo” group of endocrine disorders in which the supposed decrease in hormonal levels is actually due to the receptor not responding sufficiently to the hormone.
Receptors (from the Latin recipere - to receive) are biological macromolecules that are designed to bind to endogenous ligands (neurotransmitters, hormones, growth factors). Receptors can also interact with exogenous biologically active substances, incl. and with medications.
When a drug interacts with a receptor, a chain of biochemical transformations develops, the final result of which is a pharmacological effect.
There are four types of receptors:
1. Receptors that directly control the function of the effector enzyme. They are associated with the plasma membrane of cells, phosphorylate cell proteins and change their activity. Receptors for insulin, lymphokines, epidermal and platelet growth factors are arranged according to this principle.
2. Receptors that control the function of ion channels. Ion channel receptors make membranes permeable to ions. N-cholinergic receptors, glutamic and aspartic acid receptors increase membrane permeability for ions + + 2+
Na, K, Ca, causing depolarization and stimulation of cell function. GABAA receptors and glycine receptors increase the permeability of membranes to Cl, causing hyperpolarization and inhibition of cell function.
3. G protein-associated receptors. When these receptors are excited, the effect on the activity of intracellular enzymes is mediated through G proteins. By changing the kinetics of ion channels and 2+ synthesis of secondary messengers (cAMP, cGMP, IP3, DAG, Ca), G proteins regulate the activity of protein kinases, which ensure intracellular phosphorylation of important regulatory proteins and the development of various effects. Among these receptors
include receptors for polypeptide hormones and mediators (m-cholinergic receptors, adrenergic receptors, histamine receptors). Receptors of types 1-3 are localized on the cytoplasmic membrane.
4. Receptors - regulators of DNA transcription. These receptors are intracellular and are soluble cytosolic or nuclear proteins. Steroid and thyroid hormones interact with such receptors. The function of receptors is to activate or inhibit gene transcription.
Receptors that ensure the manifestation of the action of certain substances are called specific.
Substances that, when interacting with specific receptors, cause changes in them leading to a biological effect are called agonists. The stimulating effect of an agonist on receptors can lead to activation or inhibition of cell function. If an agonist, interacting with receptors, causes the maximum effect, then it is a full agonist. In contrast to the latter, partial agonists, when interacting with the same receptors, do not cause the maximum effect.
Substances that bind to receptors but do not stimulate them are called antagonists. Their internal activity is zero. Their pharmacological effects are due to antagonism with endogenous ligands (mediators, hormones), as well as with exogenous agonist substances. If they occupy the same receptors with which agonists interact, then we are talking about competitive antagonists; if other parts of the macromolecule are not related to a specific receptor, but are interconnected with it, then they speak of non-competitive antagonists.
Agonists can be endogenous(such as hormones and neurotransmitters) and exogenous(medicines). Endogenous agonists are normally produced within the body and mediate receptor function. For example, dopamine is an endogenous dopamine receptor agonist.
Physiological agonist is a substance that causes a similar response, but acts on a different receptor.
Range of effects
Agonists vary in the strength and direction of the physiological response they produce. This classification is not related to the affinity of the ligands and is based only on the magnitude of the receptor response.
Mechanism
If the activation of a receptor requires interaction with several different molecules, the latter are called coagonists. An example is NMDA receptors, which are activated by the simultaneous binding of glutamate and glycine.
Irreversible An agonist is called if, after binding to it, the receptor becomes permanently activated. In this case, it does not matter whether the ligand forms a covalent bond with the receptor or whether the interaction is non-covalent but extremely thermodynamically favorable.
Selectivity
Selective An agonist is called if it activates only one specific receptor or subtype of receptors. The degree of selectivity may vary: dopamine activates five different receptor subtypes but does not activate serotonin receptors. Currently, there is experimental evidence of the possibility of different interactions of the same ligands with the same receptors: depending on the conditions, the same substance can be a full agonist, antagonist or inverse agonist.
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Pharmacodynamics
Pharmacodynamics studies the biochemical and physiological effects of drugs on the human body, the mechanism of their action and the relationship between the concentration of the drug and its effect.
The activity of most cardiovascular drugs is mainly due to interaction with enzymes, structural or transport proteins, ion channels, hormone receptor ligands, neuromodulators and neurotransmitters, as well as cell membrane rupture (general anesthetics) or chemical reactions (cholestyramine, cholesterol-binding substances, active as chelate compounds). Enzyme binding alters the production or metabolism of key endogenous substances: acetylsalicylic acid irreversibly inhibits the enzyme prostaglandin synthase (cyclooxygenase), thereby preventing the development of an inflammatory response; ACE inhibitors prevent the production of angiotensin II and at the same time suppress the degradation of bradykinin, therefore its concentration increases and the vasodilating effect increases; cardiac glycosides inhibit the activity of H+, K+-ATPase.
Agonism and antagonism
Most drugs act as ligands that bind to receptors responsible for cellular effects. Binding to the receptor can cause its normal activation (agonist, partial agonist), blockade (antagonist), or even reverse action (inverse or reverse agonist). The binding of a ligand (LG) to a receptor occurs according to the law of mass action, and the binding-dissociation ratio can be used to determine the equilibrium concentration of bound receptors. The response to the drug depends on the number of receptors bound (occupation). The relationship between the number of occupied receptors and the pharmacological effect is usually nonlinear.
The basic principles of drug-receptor interaction are based on the assumption that the agonist reversibly interacts with the receptor and, therefore, induces its effect. Antagonists bind to the same receptors as agonists, but usually have no effect other than interfering with the binding of agonist molecules to the receptor and, accordingly, suppressing the effects mediated by the latter. Competitive antagonists bind reversibly to receptors. If antagonists are able to reduce the maximum effects of agonists, then the antagonism is considered non-competitive or irreversible. Experimental pharmacology has shown that some angiotensin II type 1 receptor blockers (ARBs) exhibit irreversible effects, but the clinical significance of this finding is debatable because, within the dose range recommended for clinical use, the irreversible effects of ARBs are small or negligible. Concentrations of agonists and antagonists in humans are never as high as in the experiment, and the effects of all antagonists are mainly competitive in nature, i.e. reversible.
Specificity (selectivity) of cardiovascular drugs
The specificity of a molecule is determined by its activity at one receptor, receptor subtype, or enzyme. Depending on the therapeutic target, specificity of the drug's action within the cardiovascular system can be achieved. For example, since voltage-gated calcium channels have only a minor effect on the tone of venous smooth muscle cells, slow calcium channel blockers serve as selective arterial dilators.
Similarly, vasopressin agonists have a vasoconstrictor effect primarily on the vessels of the internal organs, so they are used in the treatment of portal hypertension. Sildenafil (phosphodiesterase type V inhibitor) has a dilating effect on the vascular bed of the penis and lungs, which may reflect the expression of this enzyme in these vascular beds. Along with their presence in target organs, receptors with similar structures are also found in other cells and tissues.
When activated, they lead to the development of known side effects: agonists of 5-HT1 receptors and vasopressin cause coronary spasm, phosphodiesterase type V inhibitors cause systemic hypotension. Moreover, as the dose is increased, a loss of specificity usually occurs. In Fig. Figure 1 shows a dose-response curve for a drug that acts on two receptors, but with different strengths. Under the influence of small doses of drugs, receptor A is specifically activated, but when high doses are used (the point where the curves converge), receptors A and B are activated equally. The selectivity of drugs is relative, not absolute.
Cardioselective β-adrenergic antagonists (β-blockers) are expected to act only on cardiac β1-adrenergic receptors, but in high doses they can also affect β2-adrenergic receptors in the bronchi and blood vessels, thereby stimulating broncho- and vasoconstriction. The selectivity of a drug can be expressed as the ratio of the relative binding strengths of different antagonists. It is obvious that targeted therapy requires drugs with a high degree of selectivity.
Agonists are able to attach to receptor proteins, changing the function of the cell, i.e. they have internal activity. The biological effect of an agonist (i.e., change in cell function) depends on the efficiency of intracellular signal transduction resulting from receptor activation. The maximum effect of agonists develops when only a part of the available receptors is bound.
Another agonist, which has the same affinity, but less ability to activate receptors and corresponding intracellular signal transmission (i.e., has less intrinsic activity), will cause a less pronounced maximum effect, even if all receptors are bound, i.e., has less efficiency. Agonist B is a partial agonist. Agonist activity is characterized by the concentration at which half the maximum effect is achieved (EC 50).
Antagonists weaken the effect of agonists by counteracting them. Competitive antagonists have the ability to bind to receptors, but the cell function does not change. In other words, they are devoid of internal activity. When present in the body at the same time, an agonist and a competitive antagonist compete to bind to the receptor. The chemical affinity and concentration of both competitors determines whether the agonist or antagonist binds more actively.
Increasing agonist concentration, it is possible to overcome the block on the part of the antagonist: in this case, the curve of the dependence of the effect on the concentration shifts to the right, to a higher concentration while maintaining the maximum effectiveness of the drug.
Models of molecular mechanisms of action of agonists and antagonists
Agonist causes the receptor to transition to an activated conformation. The agonist binds to the receptor in the non-activated conformation and causes its transition to the activated state. The antagonist attaches to an inactive receptor and does not change its conformation.
Agonist stabilizes the spontaneously occurring activated conformation. The receptor is capable of spontaneously transitioning to an activated conformation state. However, usually the statistical probability of such a transition is so small that spontaneous cell excitation cannot be determined. Selective binding of the agonist occurs only to the receptor in the activated conformation and thereby favors this state.
Antagonist is able to bind to a receptor that is only in an inactive state, prolonging its existence. If the system has low spontaneous activity, adding an antagonist has little effect. However, if the system exhibits high spontaneous activity, the antagonist can cause an effect opposite to that of the agonist - the so-called inverse agonist. A “true” agonist without intrinsic activity (neutral agonist) has equal affinity for the activated and non-activated conformations of the receptor and does not change the basal activity of the cell.
According to this models, a partial agonist has less selectivity for the activated state: however, it also binds to some extent to the receptor in the non-activated state.
Other types of antagonism. Allosteric antagonism. The antagonist binds beyond the site of attachment of the agonist to the receptor and causes a decrease in the affinity of the agonist. The latter increases in the case of allosteric synergism.
Functional antagonism. Two agonists acting through different receptors change the same variable (diameter) in opposite directions (adrenaline causes expansion, histamine causes contraction).
