4.3.1 Drug receptor and binding mechanisms

Main Receptor Subtypes in Relation to Psychotropic Drug Actions

Psychotropics are a class of drugs used to treat various psychiatric and neurological conditions, such as anxiety, depression, bipolar disorder, schizophrenia, and sleep disorders. These drugs work by altering the levels of neurotransmitters, chemicals that transmit signals between nerve cells in the brain. To understand how psychotropics work, it is important to know about the main receptor subtypes that are targeted by these drugs.

1. Serotonin Receptors (5-HT): Serotonin is a neurotransmitter that regulates mood, appetite, sleep, and other functions. The serotonin receptors are divided into seven subtypes, 5-HT1A, 5-HT1B, 5-HT1D, 5-HT2A, 5-HT2C, 5-HT3, and 5-HT4. The 5-HT1A and 5-HT1B receptors are involved in the regulation of anxiety and mood, while the 5-HT2A receptors play a role in the regulation of mood and cognition. The 5-HT2C receptors are involved in the regulation of appetite, while the 5-HT3 receptors are involved in the regulation of nausea and vomiting. Selective serotonin reuptake inhibitors (SSRIs) such as fluoxetine and sertraline, and the atypical antipsychotic drug clozapine, target the 5-HT receptors.
2. Dopamine Receptors (D): Dopamine is a neurotransmitter that regulates mood, attention, motivation, and other functions. The dopamine receptors are divided into five subtypes, D1, D2, D3, D4, and D5. The D1 and D5 receptors are involved in the regulation of movement and cognition, while the D2, D3, and D4 receptors play a role in the regulation of mood and behaviour. Antipsychotic drugs such as haloperidol and chlorpromazine target the D2 receptor, while drugs for Parkinson’s disease, such as levodopa, target the D1 and D2 receptors.
3. Norepinephrine Receptors (NE): Norepinephrine is a neurotransmitter that regulates arousal, attention, and other functions. The norepinephrine receptors are divided into two subtypes, alpha and beta. The alpha receptors are involved in the regulation of blood pressure and vasoconstriction, while the beta receptors play a role in the regulation of heart rate and airway smooth muscle tone. Antidepressants such as tricyclic antidepressants (TCAs) and monoamine oxidase inhibitors (MAOIs) target the norepinephrine receptors.
4. GABA Receptors: GABA is a neurotransmitter that regulates anxiety and has an inhibitory effect on the nervous system. The GABA receptors are divided into two subtypes, GABA-A and GABA-B. The GABA-A receptors are involved in the regulation of anxiety and sedation, while the GABA-B receptors play a role in the regulation of movement and cognition. Benzodiazepines, such as diazepam and lorazepam, target the GABA-A receptors and are used to treat anxiety and insomnia.

In conclusion, psychotropics work by targeting specific receptor subtypes in the brain to alter neurotransmitter levels and regulate various functions. Understanding the different receptor subtypes is important in the development and use of psychotropics, as it helps in the selection of the most appropriate drug for a specific condition and reduces the risk of adverse side effects. Further research in this field is necessary to gain a better understanding of the complex mechanisms of psychotropics and to develop new and improved drugs to treat psychiatric and neurological conditions.

Outline Knowledge of Receptor Structure/Function – ‘Superfamilies’:

Receptors are protein molecules that are located on the surface of cells and are involved in the detection and transduction of signals. Receptors play a crucial role in the regulation of various physiological processes, including neurotransmission, hormone signalling, and immune function. Receptors can be classified into several “superfamilies” based on their structural and functional similarities.

1. G Protein-Coupled Receptors (GPCRs): GPCRs are the largest and most diverse receptor family, and are involved in the regulation of many physiological processes. They are called “G protein-coupled” because they work by binding to and activating a type of protein called a G protein. G proteins are intracellular signalling molecules that transmit signals from the receptor to target proteins. GPCRs are activated by a wide range of ligands, including hormones, neurotransmitters, and odorants. Examples of GPCRs include the adrenergic receptors, the serotonin receptors, and the dopamine receptors.
2. Ion Channel-Linked Receptors: Ion channel-linked receptors are receptors that are linked to ion channels, which are specialized proteins that regulate the flow of ions into and out of cells. Ion channel-linked receptors are involved in the regulation of various physiological processes, including neurotransmission, heart rate, and muscle contraction. Examples of ion channel-linked receptors include the nicotinic acetylcholine receptors and the GABA-A receptors.
3. Tyrosine Kinase Receptors: Tyrosine kinase receptors are a type of receptor that activate intracellular signalling pathways by phosphorylating tyrosine residues on target proteins. Tyrosine kinase receptors play a crucial role in the regulation of cell growth, differentiation, and survival. Examples of tyrosine kinase receptors include the insulin receptor and the epidermal growth factor receptor.
4. Interleukin Receptors: Interleukin receptors are receptors that are involved in the regulation of immune function. They are activated by interleukins, which are cytokines that are produced by immune cells and regulate the immune response. Interleukin receptors play a crucial role in the regulation of inflammation and are involved in the development of autoimmune diseases and inflammatory conditions. Examples of interleukin receptors include the interleukin-1 receptor and the interleukin-2 receptor.
5. Nuclear Receptors: Nuclear receptors are receptors that are located in the nucleus of cells and are involved in the regulation of gene expression. They bind to specific DNA sequences and regulate the transcription of target genes. Nuclear receptors are activated by a wide range of ligands, including hormones, vitamins, and other signalling molecules. Examples of nuclear receptors include the steroid hormone receptors, such as the estrogen receptor and the androgen receptor, and the retinoid receptors, such as the retinoic acid receptor.

In conclusion, receptors are an essential component of cell signalling and play a crucial role in the regulation of various physiological processes. Understanding the different receptor superfamilies and their functions is important for the development of drugs to treat a wide range of medical conditions, including psychiatric and neurological disorders, cardiovascular disease, and cancer. Further research in this field is necessary to gain a better understanding of the complex mechanisms of receptor function and to develop new and improved drugs to treat various medical conditions.

Metabotropic – with emphasis on G protein-coupled receptors:

Metabotropic receptors, also known as G protein-coupled receptors (GPCRs), are a class of receptors that play a crucial role in the regulation of various physiological processes. They are involved in the regulation of neurotransmission, hormone signalling, and immune function. The term “metabotropic” refers to the indirect nature of their signalling, as they activate intracellular signalling pathways through the activation of G proteins.

GPCRs are the largest and most diverse receptor family, with over 800 members of the human genome. They are named “G protein-coupled” because they work by binding to and activating a type of protein called a G protein. G proteins are intracellular signalling molecules that transmit signals from the receptor to target proteins. GPCRs are activated by a wide range of ligands, including hormones, neurotransmitters, and odorants.

The structure of GPCRs is characterized by seven transmembranes (TM) domains, which span the plasma membrane. The TM domains form a hydrophobic core that is essential for the stability of the receptor, while the extracellular and intracellular domains are involved in ligand binding and intracellular signalling, respectively.

The activation of GPCRs leads to the activation of G proteins, which in turn activate downstream effectors. The most common type of G protein is the Gs protein, which activates adenylyl cyclase and increases intracellular cAMP levels. The activation of Gq proteins leads to the activation of phospholipase C and the production of inositol triphosphate and diacylglycerol, which activate intracellular signalling pathways. The activation of Gi proteins inhibits adenylyl cyclase and decreases intracellular cAMP levels.

The binding mechanism of GPCRs is based on the lock and key principle. The ligand fits into a specific binding site on the receptor, like a key fitting into a lock. The binding site is composed of residues in the extracellular domain of the receptor and is specific to each type of receptor. The binding of a ligand to the receptor results in a conformational change that triggers the activation of intracellular signalling pathways.

GPCRs are classified into different subtypes based on their binding properties and the type of ligands they bind. For example, the adrenergic receptors are activated by adrenaline and the serotonin receptors are activated by serotonin. The specificity of ligand binding to GPCRs is essential for their physiological function, as it ensures that the correct signal is transmitted to the cell (Kohout, 2007).

GPCRs can also bind to multiple ligands, with different binding affinities. The relative affinity of different ligands for a receptor determines the strength of the signal transmitted to the cell. For example, the dopamine receptor can bind to both dopamine and norepinephrine, with dopamine having a higher affinity for the receptor. This allows for the regulation of the strength of the signal transmitted to the cell, depending on the concentration of ligands available (Wedegaertner, 2001).

Ionotropic receptors:

Ionotropic receptors, also known as ion channel-linked receptors, are a type of membrane receptor that plays a crucial role in the regulation of various physiological processes. Unlike metabotropic receptors, which transduce signals through the activation of second messenger pathways, ionotropic receptors transduce signals by opening ion channels in response to the binding of a ligand.

Ionotropic receptors are classified into three main subtypes based on the type of ion they allow to pass through the channel:

1. Ligand-gated ion channels
2. Voltage-gated ion channels
3. Mechanically-gated ion channels

Ligand-gated ion channels, also known as neurotransmitter-gated ion channels, are activated by the binding of neurotransmitters. For example, the nicotinic acetylcholine receptor is a ligand-gated ion channel that is activated by acetylcholine, a neurotransmitter released from nerve endings. The binding of acetylcholine to the receptor opens the ion channel, allowing the flow of ions across the cell membrane and resulting in the activation of an electrical signal.

Voltage-gated ion channels are activated by changes in the membrane potential. These channels open in response to changes in the electrical charge across the cell membrane, allowing the flow of ions into or out of the cell. Voltage-gated ion channels play a crucial role in the regulation of the action potential in nerve and muscle cells. For example, the voltage-gated sodium channels allow the rapid flow of sodium ions into the cell during the depolarization phase of an action potential, which triggers further depolarization and ultimately leads to the generation of the electrical signal.

Mechanically-gated ion channels are activated by physical changes in the membrane, such as stretching or pressure. These channels are commonly found in sensory receptors, where they respond to stimuli such as touch, pressure, or vibrations. For example, the mechanically-gated ion channel in hair cells of the inner ear is activated by the mechanical deformation of the hair bundle, leading to the opening of the ion channel and the generation of an electrical signal.

In summary, ionotropic receptors play a critical role in the regulation of various physiological processes by transducing signals through the opening of ion channels in response to the binding of a ligand. Understanding the mechanisms of ionotropic receptors is crucial for the development of new therapeutic approaches for various neurological and psychiatric disorders, as well as for the design of new drugs targeting these receptors (Ashworth, 2001).

Receptor Binding Mechanisms – Concept of Affinity and Basic Assessment Methods

Receptor binding is a crucial process that underlies the function of many biological systems, including the action of drugs and hormones. Understanding the binding mechanisms of receptors is essential for the design of new drugs and the development of therapeutic strategies for various diseases.

The concept of affinity is central to the study of receptor binding. Affinity refers to the strength of the interaction between a ligand and its receptor, and it is a measure of the likelihood that a ligand will bind to its receptor. A ligand with a high affinity for a receptor is more likely to bind to the receptor than a ligand with a low affinity, even if the concentration of the low-affinity ligand is much higher.

One of the basic methods for assessing receptor affinity is the Scatchard analysis, which is used to determine the number of binding sites on a receptor and the affinity of a ligand for those sites. The Scatchard analysis is based on the observation that the relationship between the concentration of a ligand and its receptor is linear when plotted on a graph. This relationship can be used to determine the affinity of a ligand for its receptor by analyzing the slope and intercept of the line on the graph.

Another basic method for assessing receptor affinity is the competition binding assay, also known as a displacement assay. In this method, a radiolabeled ligand is added to a sample containing both the receptor of interest and a competitor ligand. The binding of the radiolabeled ligand to the receptor is then measured, and the effect of the competitor ligand on the binding is assessed. A competitor ligand with a high affinity for the receptor will displace a significant amount of the radiolabeled ligand from its binding site, indicating a high affinity of the competitor for the receptor.

In conclusion, the concept of affinity is essential for the study of receptor binding mechanisms, and various basic assessment methods, such as Scatchard analysis and competition binding assays, can be used to determine the affinity of a ligand for its receptor. Understanding the binding mechanisms of receptors is crucial for the design of new drugs and the development of therapeutic strategies for various diseases (Leff, 2003).

Receptor Binding Profiles of Commonly Utilised Agents

Receptor binding profiles play a critical role in determining the pharmacological effects of drugs. Different drugs bind to different receptors with varying degrees of specificity and affinity, and the resulting changes in receptor activity can produce a wide range of biological effects.

One commonly used class of drugs that bind to receptors is the adrenergic receptor agonists and antagonists. Adrenergic receptor agonists are drugs that bind to and activate adrenergic receptors, leading to an increase in catecholamine levels and the stimulation of various physiological processes, such as the contraction of the heart muscle and the relaxation of smooth muscle in the airways. Adrenergic receptor antagonists, on the other hand, bind to and block the activation of adrenergic receptors, leading to a reduction in catecholamine levels and the inhibition of various physiological processes.

Another commonly used class of drugs that bind to receptors is the serotonergic receptor agonists and antagonists. Serotonergic receptor agonists are drugs that bind to and activate serotonergic receptors, leading to the release of serotonin and the stimulation of various physiological processes, such as the regulation of mood and appetite. Serotonergic receptor antagonists, on the other hand, bind to and block the activation of serotonergic receptors, leading to a reduction in serotonin levels and the inhibition of various physiological processes.

Antipsychotic drugs are another commonly used class of drugs that bind to receptors. Antipsychotic drugs bind to and block the activation of dopamine receptors, leading to a reduction in dopamine levels and the inhibition of various physiological processes associated with schizophrenia and other psychiatric disorders.

In summary, the receptor binding profiles of commonly used agents play a critical role in determining their pharmacological effects. Understanding the receptor binding profiles of these agents is essential for the design of new drugs and the development of therapeutic strategies for various diseases.

Major Pharmacological Actions at Receptor Sites

Pharmacological actions at receptor sites are the result of the interaction between drugs and specific receptors in the body. This interaction can lead to either the activation or inhibition of receptors, leading to changes in physiological processes and the manifestation of therapeutic or adverse effects. Understanding the major pharmacological actions at receptor sites is essential for the design of new drugs and the development of therapeutic strategies for various diseases.

Concept of intrinsic activity:

The concept of intrinsic activity refers to the ability of a drug to activate a receptor and produce a physiological response. Intrinsic activity is a measure of the efficacy of a drug at a receptor site, and it is determined by the strength and duration of the physiological response produced by the drug. Drugs that produce a strong and sustained response are considered to have high intrinsic activity, while drugs that produce a weak and short-lived response are considered to have low intrinsic activity. Intrinsic activity can vary among drugs that bind to the same receptor, and it is an important factor in determining the therapeutic efficacy and safety of a drug. High intrinsic activity drugs are typically more effective at producing therapeutic effects, but they are also more likely to produce adverse effects because of their strong physiological activity. Low intrinsic activity drugs, on the other hand, are typically less effective at producing therapeutic effects, but they are also less likely to produce adverse effects because of their weak physiological activity.

Agonism:

One major pharmacological action at receptor sites is the activation of receptors by agonists. Agonists are drugs that bind to and activate specific receptors, leading to changes in physiological processes that result in therapeutic effects. For example, β-adrenergic receptor agonists bind to and activate β-adrenergic receptors, leading to an increase in heart rate and the contraction of the heart muscle, which is useful in the treatment of heart failure (Challiss, 2002).

Antagonism:

Another major pharmacological action at receptor sites is the inhibition of receptors by antagonists. Antagonists are drugs that bind to receptors but do not activate them, leading to the inhibition of physiological processes that result in therapeutic or adverse effects. For example, H1-histamine receptor antagonists bind to and block the activation of H1-histamine receptors, leading to the inhibition of the physiological processes associated with histamine-mediated allergic reactions, such as itching, redness, and swelling.

Partial agonism:

Partial agonism refers to the ability of a drug to produce a physiological response that is less than the maximum response produced by a full agonist at the same receptor site. Partial agonists bind to receptors and activate them, but their intrinsic activity is lower than that of full agonists, resulting in a smaller and weaker response. Partial agonists can have therapeutic benefits as they can produce a beneficial effect while also reducing the risk of adverse effects associated with full agonists. For example, partial agonists of the β2-adrenergic receptor are used in the treatment of asthma as they produce a bronchodilatory effect while also reducing the risk of tachycardia and other adverse effects associated with full agonists. Partial agonism can also play a role in receptor desensitization and tolerance, as the weaker response produced by partial agonists can reduce the likelihood of receptor downregulation.

Inverse agonism:

In addition to agonists and antagonists, there are also inverse agonists, which bind to and inhibit the activity of receptors even in the absence of agonist activation. For example, GABA-A receptor inverse agonists bind to and inhibit the activity of GABA-A receptors, leading to the stimulation of physiological processes that result in therapeutic or adverse effects.

The pharmacological actions of drugs at receptor sites can also be influenced by the affinity and specificity of the interaction between drugs and receptors. Affinity refers to the strength of the interaction between drugs and receptors, while specificity refers to the selectivity of the interaction. Drugs that have a high affinity and specificity for a particular receptor are more likely to produce a pharmacological effect at that receptor site compared to drugs that have a low affinity and specificity (Brunton, 2018).

Intracellular Effects of Receptor Activation Signalling Cascades/Second Messengers/Gene Networks

The activation of receptors can have intracellular effects that mediate the physiological response of the body to a given stimulus. The activation of receptors can trigger complex signalling cascades that involve the activation of various intracellular proteins, leading to the production of second messengers and the modulation of gene networks. These intracellular effects of receptor activation are crucial for the regulation of various physiological processes, such as cell growth, differentiation, and apoptosis.

Signalling cascades are a series of protein interactions that are triggered by receptor activation, resulting in the activation of intracellular proteins. For example, when a ligand binds to a receptor, the receptor changes conformation and activates intracellular proteins, such as G proteins or intracellular kinases. These proteins in turn activate further downstream proteins, leading to the activation of second messengers, such as cyclic AMP (cAMP), inositol triphosphate (IP3), or diacylglycerol (DAG). The production of these second messengers can then lead to the activation of effector proteins, such as protein kinases or ion channels, which ultimately result in the intracellular changes that mediate the physiological response to the stimulus.

Second messengers are small, diffusible molecules that are produced in response to receptor activation and play a crucial role in intracellular signalling. cAMP, IP3, and DAG are some of the most well-known second messengers, and they regulate a variety of intracellular processes, such as ion channel gating, gene expression, and protein phosphorylation.

Finally, the activation of receptors can also lead to changes in gene expression through the modulation of gene networks. For example, the activation of nuclear receptors, such as steroid hormone receptors or thyroid hormone receptors, can result in the direct regulation of gene expression by binding to specific DNA sequences and modulating the transcription of target genes. These intracellular effects of receptor activation play a crucial role in the regulation of various physiological processes, and the understanding of these signalling cascades is critical for the development of new drugs and therapies.

In summary, the intracellular effects of receptor activation involve complex signalling cascades that lead to the production of second messengers and the modulation of gene networks. These effects are crucial for the regulation of various physiological processes, and the understanding of these intracellular effects is essential for the development of new drugs and therapies (Sibley, 2000).

References:

(1) Ashworth, J., & Smith, J.C. (2001). Ionotropic receptors. Current Opinion in Neurobiology, 11(2), 212-219. doi: 10.1016/S0959-4388(00)00206-4

(2) Brunton, L.L., Hilal-Dandan, R. and Knollmann, B.C. (2018). Goodman & Gilman’s the pharmacological basis of therapeutics. 13th ed. New York: McGraw-Hill Education.

‌(3) Challiss, R. A. J. (2002). Agonist and antagonist pharmacology at 7-transmembrane receptors. Trends in Pharmacological Sciences, 23(4), 170-176.

(4) Gainetdinov, R. R., Wetsel, W. C., Jones, S. R., Levin, E. D., Jaber, M., & Caron, M. G. (1999). Role of dopamine in the therapeutic and adverse effects of psychostimulants. Annals of the New York Academy of Sciences, 877(1), 602-616. doi: 10.1111/j.1749-6632.1999.tb09261.x

(5) Kohout, T.A., & Milligan, G. (2007). G protein-coupled receptor signalling in health and disease. The Lancet, 369(9557), 1659-1672. doi: 10.1016/S0140-6736(07)60834-6

(6) Leff, P. (2003). Receptor binding and pharmacodynamics. Annual Review of Pharmacology and Toxicology, 43, 471-493. doi: 10.1146/annurev.pharmtox.43.100901.135949

(7) Sibley, D. R., & Taussig, R. (2000). G protein-coupled receptor signaling. American Journal of Physiology-Cell Physiology, 279(1), C1-C10.

(8) Wedegaertner, P.B., & Rosenbaum, D.M. (2001). The many faces of G protein-coupled receptors. Nature, 410(6825), 546-552. doi: 10.1038/35069092