Receptor agonists- drugs that stimulate receptors are similar to natural mediators or hormones. Their value in pathological conditions lies in the fact that they are more stable than true mediators in relation to destructive substances, therefore their action is longer than that of natural substances, the effects of which they imitate.

At the beginning of this century, it was suggested that some drugs cause effects as a result of binding to specialized receptors on cells. The fact that curare eliminates muscle contraction caused by nicotine and does not prevent contraction caused by its electrical stimulation led Langley (1905) to conclude that both substances act as a result of the formation of a complex with a certain component on the muscle cell, but not with contraction. They called it a receptor or receptor. In subsequent years, the concept of "receptor" was used as the basis for a concept that allows not only to discuss the mechanisms of action of known drugs, but also to search for new ones. quantitation receptors and the study of their distribution became possible after it was found that snake venom α-toxin (which can be radioactively labeled) selectively binds to acetylcholine receptors at synapses in skeletal muscle. Using electron micrographs, receptor molecules were identified in this tissue. It became obvious that the classical concept, according to which the relationship between a substance and a receptor was considered as a "key and lock", is too limited. The method using radioligands makes it possible to determine the amount and study the binding ability of receptors both on whole cells and in preparations prepared from their shells.

It was found that the number of receptors is not constant, but changes under different circumstances. It decreases with prolonged exposure to the antagonist tissue, which can lead to the development of tachyphylaxis, i.e. to the loss of effectiveness with repeated frequent use of the drug, for example, the bronchodilatory effect of sympathomimetics in bronchial asthma. Prolonged exposure to an agonist is accompanied by the formation of new receptors. In this regard, the rapid cancellation of beta-blockers in patients suffering from angina or arrhythmia may be accompanied by a deterioration in the condition, since catecholamines circulating in the blood have a stronger effect due to an increase in the number of beta-adrenergic receptors.
Most receptors are protein molecules. When bound to an agonist receptor the conformation of the protein molecule changes, which is accompanied by a change in intracellular processes that determine the response to the drug. For example, activation of beta-adrenergic receptors by catecholamine (primary messenger) increases the activity of adenylate cyclase, which accelerates the formation of cAMP (secondary messenger), which regulates the activity of several enzymatic systems that activate the cell. The effect of a drug on the receptor can also be mediated by affecting the function of membrane ion channels closely associated with the receptor (for example, with the nicotine-sensitive acetylcholine receptor), or by changing the level of intracellular calcium (for example, the realization of some effects through muscarinic-sensitive receptors).

Receptor agonists

Receptor agonists- drugs that stimulate receptors are similar to natural mediators or hormones. Their value in pathological conditions lies in the fact that they are more stable than true mediators in relation to destructive substances, therefore their action is longer than that of natural substances, the effects of which they imitate. For example, the bronchodilatory effect of salbutamol is longer than that of epinephrine.

Receptor antagonists

Receptor antagonists (blockers) are close to natural agonists, so the receptor "recognizes" them, but, occupying the receptor, antagonists do not activate it, while the natural agonist cannot activate it. Drugs that occupy and do not activate the receptor are called pure antagonists .
partial agonists. Some drugs that block the receptor are also partially capable of stimulating it, i.e., they have the properties of both an antagonist and an agonist. Their effects depend on the circumstances, for example, nalorphine at moderate doses acts as an antagonist to opioids in relation to their depressant effect on the respiratory center, but at high doses it can increase respiratory depression. In this regard, with the advent of naloxone, a pure antagonist, nalorphine has lost its clinical significance. Substances such as pentazocine are referred to as agents with partial agonist properties. Pindolol and oxprenolol are beta-blockers with these properties. They are often called beta-blockers with internal sympathomimetic activity, in contrast to propranolol (anaprilin), which does not have the properties of an agonist and therefore is a pure antagonist. The difference between them in clinical signs quite significant, since in patients at rest, propranolol (anaprilin) ​​noticeably slows down the pulse, unlike pindolol, despite the fact that both drugs protect the body from the effects of changing concentrations of catecholamines in the blood, as they block the beta receptor. In this regard, during physical exertion, both drugs equally eliminate reflex tachycardia. It is possible that under certain conditions such differences in action may be of therapeutic importance.

Receptor binding

If the binding to the receptor is weak (hydrogen, van der Waals, or electrostatic bonds), then it is reversible, but if it is strong (covalent), then it is irreversible.
Reversible receptor-binding antagonist, can be displaced from this connection according to the law of mass action, according to which the speed chemical reaction proportional to the concentration of reactants. When the concentration of the agonist is increased sufficiently (competition), the receptor response is restored. This phenomenon is often observed in clinical practice. If a patient taking beta-blockers has an increased pulse rate during exercise compared to its frequency at rest, this indicates the ability of his sympathetic nervous system release the amount of noradrenaline (agonist) that eliminates the blocking effect of the used dose of the drug. An increase in the dose of a beta-blocker may limit or even completely eliminate exercise-induced tachycardia, which indicates a greater severity of the blockade, which increased due to a large number a drug that can compete with an endogenous mediator. Because the agonist and antagonist compete for binding to the receptor according to the law of mass action, these relationships of drugs are called competitive antagonism (for example, the use of competitive antagonists in case of an overdose of beta-blockers). At graphic image The dependence of effect on the logarithm of the dose and using data from the study of the response to the agonist, mediated through the receptor on isolated tissues, or from the functional response of the body, an S-shaped (sigmoid) curve is obtained, the central part of which forms a straight line. If the measurements are carried out in the presence of an antagonist and the curve parallel to the first one shifts to the right, this indicates a competitive interaction between the agonist and antagonist - competitive antagonism .
Phenoxybenzamine is a drug that binds irreversibly to alpha-adrenergic receptors. Since it cannot be displaced from the receptor, increasing the concentration of the agonist cannot fully restore the response to receptor stimulation. Antagonism of this type is called irreversible. The curves plotting the log dose-effect for an agonist in the absence and presence of a non-competitive antagonist are not parallel. Thus, some toxins act, for example, alpha-bungarotoxin, which is part of the venom of some snakes, irreversibly binds the acetylcholine receptor and is therefore used in pharmacological studies. Normalization of the reaction after irreversible binding occurs only after the elimination of the drug substance from the body and the synthesis of new receptors, so the effect of such substances continues even after the cessation of their administration.

Mechanism of drug action based on receptor regulation

The reaction of cells is provided by receptors. into the structure and Chemical properties Each chemical regulator has specific biological information embedded in it. In order for it to be perceived by the cell, it must be deciphered, just as a radio receiver deciphers exactly those radio waves to which it is tuned. The receptor to a certain extent resembles the active site of the enzyme, i.e. it is a macromolecular site, complementary in its configuration and distribution of ionic charges to the corresponding hormone. However, while in the substrate, when interacting with the enzyme, chemical changes, and the enzyme does not change, the hormone also does not change when interacting with the receptor, but their interaction leads to a change in the receptor. After changes in the structure and distribution of charges in the receptor, a directed change in cellular activity begins.
Like enzymes, receptors serve as a common site for the action of drugs. Under physiological conditions, selective chemical effects are directed to enzymes and receptors, and if the drug contains information that is sufficiently understandable to the cells, it will be able to "deceive" the body's regulatory mechanism. Just as enzyme inhibitors such as allopurinol are often very similar in chemical composition with a common substrate, receptor antagonists are similar to natural hormones. Understanding the physiological function of a specific hormone-receptor system can be used to suggest what properties a new substance interfering with the mechanisms of regulation (antagonist) should have. Numerous examples of this kind of speculation are known, but there is also a case that led to the creation of propranolol (inderal, anaprilin), effective in heart disease and severe hypertension.
A person can live several months without food and several days without water, but is not able to endure even a few minutes without air and oxygen. When the oxygen supply is cut off, the heart is the first to suffer. It enters the heart muscle through the arteries, through which blood passes mainly during the short pause between contractions. The delivery of oxygen is so important that the heart has its own dedicated blood supply, the coronary arteries. Without oxygen, the heart muscle stops contracting and dies. The coronary arteries are the heart's own life support system. To increase the activity of the body, whether it be physical activity or excitement, the heart reacts with an increase in the frequency and intensity of contractions, which is due to the release of norepinephrine by special (sympathetic) nerve endings in the fibers of the heart muscle. In order to do this extra work, the heart needs more oxygen, so the coronary arteries must deliver blood faster. Normally, the arteries do this, like a faucet, expanding their lumen. However, with a disease, thickenings appear on the inner lining of the arteries, which narrows their openings to such an extent that the blood flow cannot increase and meet the body's needs for oxygen (as in the formation of plaque in a water pipe: no matter how much you open the tap, the water flow will not increase) . A person feels the first sign of trouble when the coronary arteries are unable to provide the heart's need for blood and oxygen, for example, during intensive physical activity. At a critical moment, when the need for oxygen exceeds the supply, pain occurs, which can be very severe - this is how an angina attack begins. The condition of the heart muscle can normalize when the additional load is stopped due to the pain that has arisen. Thus, the work of the heart is reduced to a level that the coronary arteries are able to maintain. The activity of the patient in this case is limited. However, irreversible changes can occur in some part of the heart muscle. Thus, myocardial infarction develops. After a fairly common heart attack, intact sections of the heart muscle can still maintain the necessary level of its pumping function, provided that enough norepinephrine is released in the nerve endings. The sad paradox of heart infarction is that the norepinephrine stimulation necessary to maintain adequate contraction also increases the likelihood of impaired cardiac muscle stimulation at the border of intact and damaged areas. Such abnormal stimulation can disrupt the coordinated contraction of the heart: its wall begins to contract spasmodically and out of sync and suddenly loses its ability to be an effective pump. This condition is called cardiac fibrillation, which usually results in sudden death, but emergency treatment (electrical shock caused by a defibrillator) helps to normalize the rhythm.
Traditionally, patients with angina pectoris are treated with nitrates, and myocardial infarction with rest and analgesics. Nitrates cause a feeling of warmth, redness of the face. It is believed that a similar expansion of blood vessels occurs in the heart muscle, which can ensure the entry into it more blood. A broad search for drugs that have the most pronounced properties to expand the coronary vessels, more selectively and for a long time, has been quite successful. The newer drugs do increase coronary blood flow, but often fail to prevent or alleviate angina! This, apparently, is not surprising: the affected arteries cannot expand in the same way as intact ones. The drug can indeed increase the blood supply to the heart muscle by causing changes in nerve reflexes. Such reflex effects can lead to an increase in myocardial oxygen demand. If it is not possible to effectively increase the oxygen supply with a drug, why not try to decrease the oxygen demand of the heart muscle? This is exactly what happens when a patient with angina pectoris gives himself rest or a patient with a heart attack observes bed rest. The problem is that norepinephrine stimulation of the heart, which largely determines its oxygen demand, is only partially controlled by exercise; excitement, fear, pain, or even physical discomfort also stimulate its function. Just rest is not enough. The idea arises to search for such drugs that could prevent the effects of norepinephrine and thus control the need for oxygen in the heart muscle.
Norepinephrine receptors are special sections of heart muscle cells that are the first to “recognize” norepinephrine and combine with it, and then change cellular enzymes that “force” the heart to contract faster and stronger. It was found that propranolol (anaprilin) ​​is “recognized” by the noradrenaline receptors of the heart cell and binds to them; at the same time, it not only does not affect the mechanisms that cause an increase in enzymatic activity in the heart, but, by binding to the receptor, prevents such an action of norepinephrine. This property of propranolol alone might be enough to make it a useful drug, but another extremely important property has been identified. The norepinephrine receptors in blood vessels appear to be different from those in the heart muscle. The former are currently attributed mainly to alpha-adrenergic receptors, while propranolol turned out to be a selective antagonist of beta-adrenergic receptors in the heart muscle. This means that it is effective in the changes that occur in the heart during physical or emotional stress, but has little effect on the nervous regulation in relation to the blood vessels. During physical exertion, the nerve endings in them, as a result of the release of norepinephrine, determine the redistribution of blood, which from the skin and internal organs begins to flow to the muscles, increasing their blood supply. propranolol does not affect this action of norepinephrine, since beta-adrenergic receptors are practically not involved in this process.
In patients with coronary insufficiency receiving propranolol, heavy physical activity may not be accompanied by pain. There is also evidence that long-term blockade of beta-adrenergic receptors increases life expectancy. A pleasant surprise in clinical trials was the effectiveness of propranolol in severe hypertension. If its action is also associated with the ability to reduce cardiac work and cardiac output during exercise (which seems likely), this will shed light on the possible origin of this widespread disease.
In this way, we are talking about a drug that not only brings relief to patients, but also provides a lot of grounds for understanding the role of norepinephrine and related hormones both in normal and pathological conditions. It is currently one of the most important aspects of drug research. They do not just bring relief to the patient, but serve as important tools for medical research, helping to understand the nature of the disease.
Another example of the effective use of new drugs is histamine. Beta-adrenergic blockers were discovered after it was found that existing antagonists (blockers of alpha-adrenergic receptors) are not able to prevent the reaction of the heart muscle to adrenaline. New histamine blockers were discovered after the inability of old antihistamines to prevent the reaction of the glands of the gastric mucosa to it. She secretes hydrochloric acid, which, contrary to popular belief, seems to play a much smaller role in digestion than in the sterilization of the upper intestine. For example, the incidence of tuberculosis is higher in individuals who do not secrete hydrochloric acid. Every time you eat, acid secretion starts in the stomach. Some individuals secrete too much of it because the stimulus is extremely strong, or perhaps because of a defect in the mechanism that stops secretion at the end of the digestion process. In any case, excessive secretion of hydrochloric acid is associated with the risk of developing gastric or duodenal ulcers. These ulcers (peptic ulcers) can cause a lot of anxiety due to pain and indigestion, or lead to serious, even fatal complications: severe bleeding or perforation of the stomach wall, in which its contents enter the abdominal cavity, resulting in peritonitis. These glands of the gastric mucosa can be removed surgically, thus blocking the secretion of acid; it is also possible to cut the nerves, which stops the stimulation of the secretion. However, after these operations, death often occurs (more than 1:200).
The endings of the nerves that the surgeon cuts secrete acetylcholine. Therefore, atropine, a competitive antagonist of acetylcholine, should cause the same effect. For many years it and related drugs have been used for peptic ulcers of the stomach, but the results have been disappointing. Doses of atropine required to reduce hydrochloric acid secretion also block other acetylcholine receptors, causing blurred vision, dryness of the mucous membranes in the mouth, and difficulty urinating. It also blocks the receptors of the nerves going to the muscles of the stomach wall, so that the evacuation from it slows down. All this neutralizes the positive effect of atropine in reducing the acidity of gastric juice. Its action is not selective enough.
In addition to acetylcholine, two other substances are found in the stomach that are powerful stimulants of its secretion: histamine and gastrin. Gastrin (a polypeptide) released from food in another part of the intestine serves as the main hormone that controls secretion in the stomach. It reaches its receptors on the cells of the gastric mucosa, coming to them from the blood, stimulates the secretion of both digestive enzymes and hydrochloric acid. Histamine is derived from a single amino acid (histidine) and is concentrated in the region of acid-secreting cells. It only stimulates the secretion of hydrochloric acid. Some researchers believe that this stimulation is mediated by the local release of histamine from its depot.
Like norepinephrine, histamine acts on two types of receptors: H1 and H2. Antihistamines used in hay fever block H1 receptors. A few years ago, antagonists were found that block H2 receptors. One of them [cimetidine (tagamet)] is currently used in the clinic. Although it is a competitive histamine antagonist, it also inhibits the action of gastrin. This is good news for patients with peptic ulcers, since gastric acid secretion can now be selectively reduced. A greater number of patients can recover faster than with drugs that block the effect of acetylcholine. They have a chance to avoid serious complications accompanying surgery. In 1985, after almost 10 years of intensive clinical use of cimetidine, no unexpected side effects were found. In doing so, medical workers have received a new tool to study the function of histamine. Given that it plays a protective role in inflammation and repair of damaged tissues, it can be assumed that the secretion
hydrochloric acid in the stomach can be seen as part of the defense system. Yet the presence of histamine in the brain is puzzling. It is synthesized in the brain, but its function is unclear. However, now that it has become possible to distinguish histamine receptors using drugs like cimetidine, there may be progress in the development of new drugs.
More and more people are beginning to understand how medicinal substances "use" the body's control mechanisms (receptors, hormones, binding sites, etc.) to ensure selectivity of action. This understanding provides hope in the future for even more brand new drugs, which will increase the number of patients who benefit from modern medicine.
However, no amount of art in obtaining more selectively active and effective drugs will lead the researcher away from the problem of their toxicity. This is the undeniable truth. The interaction of the drug with its target is determined by its correspondence to the active site on the cell membrane and the probability that the chaotic movement of molecules contributes to the contact of the drug molecule with the active site. The possibility of this contact is determined mainly by the number of molecules. In cases where drug molecules have a high affinity for active sites on the cell wall, even a small number of them can provide interaction. However, as the concentration of the drug increases, its effective interaction with active sites that have a lower affinity for the drug is possible. This may cause its additional effects, including undesirable and even harmful. The drug becomes less selective regardless of whether the substance belongs to natural compounds or is synthesized.

Molecular basis of action of agonists and antagonists of steroid receptors

Characteristics of agonists

Agonists can be endogenous(e.g. hormones and neurotransmitters) and exogenous(medication). Endogenous agonists are normally produced within the body and mediate receptor function. For example, dopamine is an endogenous dopamine receptor agonist.

Physiological agonist called a substance that causes a similar response, but acting on a different receptor.

Spectrum of effects

Spectrum of agonist effects

Agonists differ in the strength and direction of the physiological response they elicit. This classification is not related to the affinity of the ligands and relies only on the magnitude of the receptor response.

Superagonist- a compound capable of inducing a stronger physiological response than an endogenous agonist. Full agonist- a compound that causes the same response as an endogenous agonist (for example, isoprenaline, a β-adrenergic agonist). In the case of a smaller response, the connection is called partial agonist(for example, aripiprazole is a partial agonist of dopamine and serotonin receptors).

If the receptor has a basal (constitutive) activity, some substances - inverse agonists- can reduce it. In particular, GABA A receptor inverse agonists have an anxiogenic or spasmodic effect, but may enhance cognition.

Mechanism

When interaction with several different molecules is required to activate a receptor, 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 named if it activates only one specific receptor or subtype of receptor. The degree of selectivity can vary: dopamine activates five different subtypes of receptors, but does not activate serotonin receptors. Currently, there are experimental confirmations 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.

Activity

Notes

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See what "Agonist" is in other dictionaries:

- (this see the previous word). Fighter. Dictionary foreign words included in the Russian language. Chudinov A.N., 1910. AGONIST Greek. agonistes, from agon, struggle. Opponent, persecutor of opinions. An explanation of 25,000 foreign words that have come into use in ... ... Dictionary of foreign words of the Russian language

Exist., number of synonyms: 3 fighter (39) persecutor (5) enemy (26) ASIS synonym dictionary ... Synonym dictionary

agonist- Small proteins or organic molecules, binding to certain cellular proteins, which are receptors, cause their conformational changes, which enhances the action of hormones, mediators, etc. ... ... Technical Translator's Handbook

AGONIST- 1. A muscle that contracts and acts in the opposite direction compared to another muscle, the antagonist; when bending the elbow, for example, the biceps is the agonist, and the triceps is the antagonist. See muscle antagonists. 2. Any drug, ... ... Dictionary in psychology

agonist- (grch agonistes) how old Grtsi wrestler, megdanџiјa, natprevaruvach in viteshki games ... Macedonian dictionary

AGONIST- (agonist) 1. Prime mover muscle, due to the contraction of which a certain movement of one or another part of the body occurs. Contraction of the agonist muscle is accompanied by relaxation of the opposing antagonist muscle. 2. Medicinal product or ... ... Explanatory Dictionary of Medicine

Receptors (from 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 biological active substances, incl. and with drugs.

When a drug interacts with a receptor, a chain of biochemical transformations develops, the end 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. According to this principle, receptors for insulin, lymphokines, epidermal and platelet growth factors are arranged.

2. Receptors that control the function of ion channels. Ion channel receptors provide membrane permeability for ions. N-cholinergic receptors, glutamine and aspartic acid increase membrane permeability for ions + + 2+

Na, K, Ca, causing depolarization and excitation of cell function. GABAA receptors, glycine receptors increase the permeability of membranes for Cl, causing hyperpolarization and inhibition of cell function.

3. Receptors associated with G-proteins. 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 second messengers (cAMP, cGMP, IP3, DAG, Ca), G-proteins regulate the activity of protein kinases, which provide 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, adrenoreceptors, 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. These receptors interact with steroid and thyroid hormones. The function of receptors is the activation or inhibition of gene transcription.

Receptors that provide 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 stimulatory 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 this 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 that are not related to a specific receptor, but are interconnected with it, then they speak of non-competitive antagonists.

Pharmacodynamics includes concepts of pharmacological effects, localization of action and mechanisms of action of drugs (i.e. ideas about how, where and how drugs act in the body). Pharmacodynamics also includes the concept of the types of drug action.

2.1. PHARMACOLOGICAL EFFECTS, LOCALIZATION AND MECHANISMS OF ACTION OF MEDICINAL SUBSTANCES

Pharmacological effects - changes in the function of organs and systems of the body caused by drugs. The pharmacological effects of drugs include, for example, an increase in heart rate, a decrease in blood pressure, an increase in the threshold of pain sensitivity, a decrease in body temperature, an increase in sleep duration, the elimination of delusions and hallucinations, etc. Each substance, as a rule, causes a number of specific pharmacological effects characteristic of it. At the same time, some pharmacological effects of drugs are useful - thanks to them, drugs are used in medical practice (main effects),

and others are not used and, moreover, are undesirable (side effects).

For many substances, the places of their predominant action in the body are known - i.e. action localization. Some substances mainly act on certain structures of the brain (antiparkinsonian, antipsychotic drugs), others mainly act on the heart (cardiac glycosides).

Thanks to modern methodological techniques, it is possible to determine the localization of the action of substances not only at the systemic and organ, but at the cellular and molecular levels. For example, cardiac glycosides act on the heart (organ level), on cardiomyocytes (cellular level), on Na + -, K + -ATPase of cardiomyocyte membranes (molecular level).

The same pharmacological effects can be produced in different ways. So, there are substances that cause a decrease in blood pressure by reducing the synthesis of angiotensin II (ACE inhibitors), or by blocking the entry of Ca 2+ into smooth muscle cells (blockers of voltage-dependent calcium channels) or by reducing the release of norepinephrine from the endings of sympathetic nerves (sympatholytics). The ways in which drugs cause pharmacological effects are defined as mechanisms of action.

The pharmacological effects of most drugs are caused by their action on certain molecular substrates, the so-called "targets".

The main molecular "targets" for drugs include receptors, ion channels, enzymes, transport systems.

Receptors

A. Properties and types of receptors. Interaction of receptors with enzymes and ion channels

Receptors are functionally active macromolecules or their fragments (mainly protein molecules - lipoproteins, glycoproteins, nucleoproteins, etc.). When substances (ligands) interact with receptors, a chain of biochemical reactions occurs, leading to the development of certain

pharmacological effects. Receptors serve as targets for endogenous ligands (neurotransmitters, hormones, other endogenous biologically active substances), but they can also interact with exogenous biologically active substances, including drugs. Receptors interact only with certain substances (having a certain chemical structure and spatial orientation), i.e. are selective, hence they are called specific receptors.

Receptors are not stable, constantly existing structures cells. Their number may increase due to the predominance of the synthesis of receptor proteins or decrease due to the predominance of the process of their degradation. In addition, receptors may lose their functional activity (desensitization), as a result, when the receptor interacts with the ligand, biochemical reactions leading to a pharmacological effect do not occur. All these processes are regulated by the concentration of the ligand and the duration of its action on the receptors. With prolonged exposure to the ligand, desensitization of receptors and / or a decrease in their number develops. (down-regulation), and, conversely, the absence of a ligand (or a decrease in its concentration) leads to an increase in the number of receptors (up-regulation).

Receptors can be located in the cell membrane (membrane receptors) or inside cells - in the cytoplasm or nucleus (intracellular receptors) (Fig. 2-1).

membrane receptors. Membrane receptors have extracellular and intracellular domains. The extracellular domain has binding sites for ligands (substances that interact with receptors). Intracellular domains interact with effector proteins (enzymes or ion channels) or have enzymatic activity themselves.

Three types of membrane receptors are known.

1. Receptors that are directly coupled to enzymes. Since the intracellular domain of these receptors exhibits enzymatic activity, they are also called enzyme receptors or catalytic receptors. Most of the receptors in this group have tyrosine kinase activity. When the receptor binds to a substance, tyrosine kinase is activated, which phosphorylates intracellular proteins and thus changes their activity. These receptors include receptors for insulin, some growth factors, and cytokines. Receptors directly associated with guanylate cyclase are known (when exposed to atrial natriuretic factor, guanylate cyclase is activated, and the content of cyclic guanosine monophosphate increases in cells).

2. Receptors that are directly coupled to ion channels consist of several subunits that penetrate the cell membrane and form an ion channel. When a substance binds to the extracellular domain of the receptor, ion channels open, resulting in a change in the permeability of cell membranes for various ions. These receptors include H-cholinergic receptors, gamma-aminobutyric acid (GABA) subtype A receptors, glycine receptors, and glutamate receptors.

The N-cholinergic receptor consists of five subunits penetrating the cell membrane. When two molecules of acetylcholine bind to two α-subunits of the receptor, the sodium channel opens and sodium ions enter the cell, causing depolarization cell membrane(in skeletal muscle this results in muscle contraction).

GABA A receptors are directly coupled to chloride channels. When receptors interact with GABA, chloride channels open and chloride ions enter the cell, causing

hyperpolarization of the cell membrane (this leads to increased inhibitory processes in the central nervous system). Glycine receptors function in the same way. 3. Receptors interacting with G-proteins. These receptors interact with enzymes and ion channels of cells through intermediary proteins (G proteins - guanosine triphosphate (GTP) binding proteins). When a substance acts on the receptor, the α-subunit of the G-protein binds to guanosine triphosphate. In this case, the G-protein-guanosine triphosphate complex interacts with enzymes or ion channels. As a rule, one receptor is coupled to several G proteins, and each G protein can simultaneously interact with several enzyme molecules or several ion channels. As a result of such an interaction, an increase (amplification) of the effect occurs.

The interaction of G-proteins with adenylate cyclase and phospholipase C has been well studied.

Adenylate cyclase is a membrane-bound enzyme that hydrolyzes ATP. As a result of ATP hydrolysis, cyclic adenosine monophosphate (cAMP) is formed, which activates cAMP-dependent protein kinases that phosphorylate cellular proteins. This changes the activity of proteins and the processes they regulate. According to the effect on the activity of adenylate cyclase, G proteins are divided into G s proteins that stimulate adenylate cyclase and G i proteins that inhibit this enzyme. An example of receptors that interact with G s proteins are β 1 -adrenergic receptors (mediate a stimulating effect on the heart of sympathetic innervation), and receptors that interact with G i proteins are M 2 -cholinergic receptors (mediate an inhibitory effect on the heart of parasympathetic innervation). These receptors are localized in the membrane of cardiomyocytes.

With stimulation of β 1 -adrenergic receptors, the activity of adenylate cyclase increases and the content of cAMP in cardiomyocytes increases. As a result, protein kinase is activated, which phosphorylates the calcium channels of cardiomyocyte membranes. Through these channels, calcium ions enter the cell. The entry of Ca 2+ into the cell increases, which leads to an increase in the automatism of the sinus node and an increase in the heart rate. Intracellular effects of the opposite direction develop with stimulation of M 2 -cholinergic receptors of cardiomyocytes, resulting in a decrease in the automatism of the sinus node and heart rate.

Phospholipase C interacts with G q -proteins, causing its activation. An example of G-coupled receptors q -proteins are adrenergic receptors of vascular smooth muscle cells (mediating the effect on the vessels of sympathetic innervation). When these receptors are stimulated, the activity of phospholipase C increases. Phospholipase C hydrolyzes phosphatidylinositol-4,5-diphosphate of cell membranes with the formation of a hydrophilic substance inositol-1,4,5-triphosphate, which interacts with calcium channels of the sarcoplasmic reticulum of the cell and causes the release of Ca 2 + into the cytoplasm. With an increase in Ca 2+ concentration in the cytoplasm of smooth muscle cells, the rate of formation of the Ca 2+ -calmodulin complex increases, which activates myosin light chain kinase. This enzyme phosphorylates myosin light chains, which facilitates the interaction of actin with myosin, and contraction of vascular smooth muscle occurs.

Receptors interacting with G-proteins also include dopamine receptors, some subtypes of serotonin (5-HT) receptors, opioid receptors, histamine receptors, receptors for most peptide hormones, etc.

intracellular receptors are soluble cytosolic or nuclear proteins that mediate the regulatory action of substances for DNA transcription. Ligands of intracellular receptors are lipophilic substances (steroid and thyroid hormones, vitamins A, D).

The interaction of a ligand (for example, glucocorticoids) with cytosolic receptors causes their conformational change, as a result, the substance-receptor complex moves to the cell nucleus, where it binds to certain regions of the DNA molecule. There is a change (activation or repression) of the transcription of genes encoding the synthesis of various functionally active proteins (enzymes, cytokines, etc.). An increase (or decrease) in the synthesis of enzymes and other proteins leads to a change in the biochemical processes in the cell and the appearance of pharmacological effects. Thus, glucocorticoids, by activating the genes responsible for the synthesis of gluconeogenesis enzymes, stimulate the synthesis of glucose, which contributes to the development of hyperglycemia. As a result of repression of genes encoding the synthesis of cytokines, intercellular adhesion molecules, cyclooxygenase, glucocorticoids have an immunosuppressive and anti-inflammatory effect. Pharmacological

the effects of substances in their interaction with intracellular receptors develop slowly (over several hours or even days).

Interaction with nuclear receptors is characteristic of thyroid hormones, vitamins A (retinoids) and D. A new subtype of nuclear receptors has been discovered - receptors activated by peroxisome proliferators. These receptors are involved in the regulation of lipid metabolism and other metabolic processes and are targets for clofibrate (a lipid-lowering drug).

B. Binding of a substance to a receptor. The concept of affinity

In order for a drug to act on a receptor, it must bind to it. As a result, a “substance-receptor” complex is formed. The formation of such a complex is carried out with the help of intermolecular bonds. There are several types of such connections.

Covalent bonds are the strongest type of intermolecular bonds. They are formed between two atoms due to a common pair of electrons. Covalent bonds most often provide irreversible binding substances, but they are not typical for the interaction of drugs with receptors.

Ionic bonds are less strong and arise between groups carrying opposite charges (electrostatic interaction).

Ion-dipole and dipole-dipole bonds are similar in character to ionic bonds. In electrically neutral drug molecules that enter the electric field of cell membranes or are surrounded by ions, the formation of induced dipoles occurs. Ionic and dipole bonds are characteristic of the interaction of drugs with receptors.

Hydrogen bonds play a very significant role in the interaction of drugs with receptors. The hydrogen atom is able to bind the atoms of oxygen, nitrogen, sulfur, halogens. Hydrogen bonds are weak, for their formation it is necessary that the molecules are at a distance of no more than 0.3 nm from each other.

Van der Waals bonds are the weakest bonds that form between any two atoms if they are at a distance of no more than 0.2 nm. As the distance increases, these bonds weaken.

Hydrophobic bonds are formed during the interaction of non-polar molecules in an aqueous medium.

The term affinity is used to characterize the binding of a substance to a receptor.

Affinity (from lat. affinis- related) - the ability of a substance to bind to a receptor, resulting in the formation of a "substance-receptor" complex. In addition, the term "affinity" is used to characterize the strength of the binding of a substance to the receptor (ie, the duration of the existence of the "substance-receptor" complex). A quantitative measure of affinity as the strength of the binding of a substance to a receptor is dissociation constant(To d).

The dissociation constant is equal to the concentration of a substance at which half of the receptors in a given system are bound to the substance. This indicator is expressed in moles / l (M). Between affinity and dissociation constant there is an inversely proportional relationship: the smaller K d , the higher the affinity. For example, if K d substance A is 10 -3 M, and K d of substance B is 10 -10 M, the affinity of substance B is higher than that of substance A.

B. Internal activity of medicinal substances. The concept of agonists and antagonists of receptors

Substances that have affinity may have intrinsic activity.

Internal activity - the ability of a substance, when interacting with a receptor, to stimulate it and thus cause certain effects.

Depending on the presence of internal activity, drugs are divided into agonists and antagonists receptors.

Agonists (from the Greek. agonistes- rival agon- wrestling) or mimetics- substances with affinity and internal activity. When interacting with specific receptors, they stimulate them, i.e. cause changes in the conformation of receptors, resulting in a chain of biochemical reactions and the development of certain pharmacological effects.

Full agonists, interacting with receptors, cause the maximum possible effect (they have maximum internal activity).

Partial agonists, when interacting with receptors, cause an effect that is less than the maximum (do not have maximum internal activity).

Antagonists (from the Greek. antagonism- rivalry, anti- against, agon- struggle) - substances with affinity, but devoid of internal activity. By binding to receptors, they prevent the action of endogenous agonists (neurotransmitters, hormones) on these receptors. Therefore, antagonists are also called receptor blockers. The pharmacological effects of antagonists are due to the elimination or weakening of the action of endogenous agonists of these receptors. In this case, there are effects opposite to the effects of agonists. Thus, acetylcholine causes bradycardia, and the antagonist of M-cholinergic receptors atropine, eliminating the effect of acetylcholine on the heart, increases the heart rate.

If antagonists occupy the same binding sites as agonists, they can displace each other from binding to the receptors. This type of antagonism is referred to as competitive antagonism, and antagonists are called competitive antagonists and. Competitive antagonism depends on the relative affinity of competing substances for a given receptor and their concentration. At sufficiently high concentrations, even a low affinity substance can displace a higher affinity substance from binding to the receptor. That's why in competitive antagonism, the effect of an agonist can be fully restored by increasing its concentration in the medium. Competitive antagonism is often used to eliminate the toxic effects of drugs.

Partial antagonists can also compete with full agonists for binding sites. By displacing full agonists from binding to receptors, partial agonists reduce their effects and, therefore, can be used instead of antagonists in clinical practice. For example, partial agonists of β-adrenergic receptors (pindolol) as well as antagonists of these receptors (propranolol, atenolol) are used in the treatment of hypertension.

Non-competitive antagonism develops when an antagonist occupies the so-called allosteric binding sites on receptors (areas of a macromolecule that are not binding sites for an agonist, but regulate receptor activity). Non-competitive antagonists change the conformation of receptors

so that they lose their ability to interact with agonists. At the same time, an increase in the concentration of an agonist cannot lead to a complete restoration of its effect. Non-competitive antagonism also occurs in the case of irreversible (covalent) binding of a substance to a receptor.

Some drugs combine the ability to stimulate one receptor subtype and block another. Such substances are referred to as antagonist agonists (for example, butorphanol is a µ antagonist and κ agonist of opioid receptors).

Other drug targets

Other "targets" include ion channels, enzymes, transport proteins.

ion channels.One of the main "targets" for drugs are voltage-gated ion channels that selectively conduct Na + , Ca 2+ , K + and other ions through the cell membrane. Unlike receptor-gated ion channels, which open when a substance interacts with a receptor, these channels are regulated by the action potential (open when the cell membrane is depolarized). Drugs can either block voltage-gated ion channels and thus disrupt the flow of ions through them, or activate, i.e. facilitate the passage of ionic currents. Most drugs block ion channels.

Local anesthetics block voltage-dependent Na + channels. Many antiarrhythmic drugs (quinidine, lidocaine, procainamide) also belong to the number of Na + -channel blockers. Some antiepileptic drugs (phenytoin, carbamazepine) also block voltage-dependent Na + channels, and their anticonvulsant activity is associated with this. Sodium channel blockers disrupt the entry of Na + into the cell and thus prevent the depolarization of the cell membrane.

Very effective in the treatment of many cardiovascular diseases (hypertension, cardiac arrhythmias, angina pectoris) were Ca 2+ channel blockers (nifedipine, verapamil, etc.). Calcium ions are involved in many physiological processes: smooth muscle contraction, generation of impulses in the sinoatrial node and conduction of excitation through the atrioventricular node, platelet aggregation, etc. Blockers of slow calcium

channels prevent the entry of calcium ions into the cell through voltage-dependent channels and cause relaxation of vascular smooth muscles, a decrease in the heart rate and AV conduction, and disrupt platelet aggregation. Some calcium channel blockers (nimodipine, cinnarizine) mainly dilate the brain vessels and have a neuroprotective effect (prevent excess Ca 2+ from entering neurons).

Both activators and blockers of potassium channels are used as medicines. Potassium channel activators (minoxidil) have been used as antihypertensive agents. They contribute to the release of potassium ions from the cell, which leads to hyperpolarization of the cell membrane and a decrease in the tone of vascular smooth muscles. As a result, there is a decrease in blood pressure. Drugs that block voltage-dependent potassium channels (amiodarone, sotalol) have found application in the treatment of cardiac arrhythmias. They prevent the release of K + from cardiomyocytes, as a result of which they increase the duration of the action potential and lengthen the effective refractory period (ERP). Blockade of ATP-dependent potassium channels in pancreatic β-cells leads to an increase in insulin secretion; blockers of these channels (sulfonylurea derivatives) are used as antidiabetic agents.

Enzymes.Many drugs are enzyme inhibitors. MAO inhibitors disrupt the metabolism (oxidative deamination) of catecholamines (norepinephrine, dopamine, serotonin) and increase their content in the central nervous system. The action of antidepressants - MAO inhibitors (for example, nialamide) is based on this principle. The mechanism of action of non-steroidal anti-inflammatory drugs is associated with the inhibition of cyclooxygenase, as a result, the biosynthesis of prostaglandins E 2 and I 2 decreases and a pro-inflammatory effect develops. Acetylcholinesterase inhibitors (anticholinesterase agents) prevent the hydrolysis of acetylcholine and increase its content in the synaptic cleft. Preparations of this group are used to increase the tone of smooth muscle organs (GIT, bladder) and skeletal muscles.

Transport systems. Drugs can act on transport systems (transport proteins) that carry molecules of certain substances or ions through cell membranes. For example, tricyclic antidepressants block the transport proteins that carry norepinephrine and serotonin across the presynaptic membrane.

wound of the nerve ending (block the reverse neuronal uptake of norepinephrine and serotonin). Cardiac glycosides block the K + -ATPase of cardiomyocyte membranes, which transports Na + from the cell in exchange for K + .

Other "targets" that drugs can act on are also possible. So, antacids neutralize the hydrochloric acid of the stomach, they are used for increased acidity of gastric juice (hyperacid gastritis, gastric ulcer).

A promising "target" for drugs are genes. With the help of selectively acting drugs, it is possible to directly influence the function of certain genes.

2.2. TYPES OF ACTION OF MEDICINAL SUBSTANCES

Distinguish the following types actions: local and resorptive, reflex, direct and indirect, main and side and some others.

The local action of the drug is in contact with the tissues at the site of its application (usually the skin or mucous membranes). For example, with surface anesthesia, a local anesthetic acts on the endings of sensory nerves only at the site of application to the mucous membrane. To provide local action, drugs are prescribed in the form of ointments, lotions, rinses, patches. When prescribing some drugs in the form of eye or ear drops, they also rely on their local action. However, a certain amount of the drug is usually absorbed from the site of application into the blood and has a general (resorptive) effect. With topical application of drugs, a reflex action is also possible.

Resorptive action (from lat. resorbeo- absorb) - the effects caused by a drug after absorption into the blood or direct injection into a blood vessel and distribution in the body. With a resorptive action, as with a local one, a substance can excite sensitive receptors and cause reflex reactions.

reflex action. Some drugs are able to excite the endings of the sensory nerves of the skin, mucous membranes (exteroreceptors), vascular chemoreceptors (interoreceptors) and cause reflex reactions from organs located at a distance from the place of direct contact of the substance with sensitive receptors. An example of excitation of exteroreceptors

skin essential mustard oil is the action of mustard plasters. Lobelin, when administered intravenously, excites vascular chemoreceptors, which leads to reflex stimulation of the respiratory and vasomotor centers.

The direct (primary) effect of the drug on the heart, blood vessels, intestines and other organs develops with a direct impact on these organs. For example, cardiac glycosides cause a cardiotonic effect (increased myocardial contractions) due to their direct effect on cardiomyocytes. The increase in diuresis caused by cardiac glycosides in patients with heart failure is due to an increase in cardiac output and improved hemodynamics. Such an action, in which the drug changes the function of some organs, affecting other organs, is referred to as an indirect (secondary) action.

Main action. The action for which the drug is used in the treatment of this disease. For example, phenytoin has anticonvulsant and antiarrhythmic properties. In a patient with epilepsy, the main action of phenytoin is anticonvulsant, and in a patient with cardiac arrhythmia caused by an overdose of cardiac glycosides, it is antiarrhythmic.

All other (except the main) effects of the drug that occur when it is taken in therapeutic doses are regarded as a side effect. These effects are often unfavorable (negative) (see the chapter "Adverse and toxic effects of drugs"). For example, acetylsalicylic acid can cause ulceration of the gastric mucosa, antibiotics from the aminoglycoside group (kanamycin, gentamicin, etc.) can cause hearing loss. Negative side effects often serve as a reason for limiting the use of a particular drug and even excluding it from the list of drugs.

The selective action of the drug is directed mainly to one organ or system of the body. Thus, cardiac glycosides have a selective effect on the myocardium, oxytocin - on the uterus, hypnotics - on the central nervous system.

The central action develops due to the direct influence of the drug on the central nervous system. The central action is characteristic of substances that penetrate the BBB. For hypnotics, antidepressants, anxiolytics, anesthetics, this is the main action. At the same time, the central action may be side (undesirable).

So, many antihistamines cause drowsiness due to the central action.

Peripheral action is due to the influence of drugs on the peripheral part of the nervous system or on organs and tissues. Curare-like drugs (peripherally acting muscle relaxants) relax skeletal muscles by blocking the transmission of excitation in neuromuscular synapses, some peripheral vasodilators dilate blood vessels, acting directly on smooth muscle cells. For substances with a primary central action, peripheral effects are usually side effects. For example, the antipsychotic drug chlorpromazine causes vasodilatation and a decrease in blood pressure (an undesirable effect) by blocking peripheral α-adrenergic receptors.

The reversible action is a consequence of the reversible binding of drugs to "targets" (receptors, enzymes). The action of such a substance can be stopped by displacing it from its connection with the "target" of another drug.

Irreversible action occurs, as a rule, as a result of strong (covalent) binding of the drug to the "targets". For example, acetylsalicylic acid irreversibly blocks cyclooxygenase, so the effect of the drug stops only after the synthesis of a new enzyme.