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| a small molecule that influences receptor availability by binding directly to the receptor protein at a specific site; a chemical that fits into the active site of a receptor protein and either activates or inhibits the physiological function of the receptor |
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| receptor activeity that occurs in the absence of agonist binding |
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| a ligand that activates a receptor upon binding |
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| drugs that are able to activate a receptor but are unable to produce the full effect of the endogenous ligand |
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| a ligand that inhibits a recept primarily by interfering with agonist binding |
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| an agent that binds to the same receptor as an agonist but induces a pharmacological response opposite that to the agonist |
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| the number of receptors bound to a ligand at any given time |
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| escribes a binding site on a receptor that is distinct from the ligand-biding site |
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| the degree to which a drug can discriminate between available receptors based on relative affinities |
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| the degree to which a receptor discriminates between binding to a structurally similar ligand |
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| the difference in free energy resulting in a kinetic barrier to the progress of a chemical reaction |
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| a highly unstable chemical species that is intermediate between substrate and product |
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| the fastest rate of product formation |
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| receptor proteins fold into a specific three dimensional structure that forms a binding site, often called a pocket, for ligands or substrates. The tertiary structure is critical for receptors as it is the arrangement o secondary folding motifs that forms the binding site. Even slight changes to the three dimensional shape, or conformation, of a receptor protein can distor the binding site so that ligands will no longer bind efficiently. |
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| the ligand binding site of a receptor is often referred to as __________ meaning that it is the site at which a ligand can activate the receptor to transmit a signal or inhibit the receptor and stop signal transmission. The presene of a molecule bound to thea ctive site of a receptor will induce a change in the conformation of the receptor protein that results in a change in activity |
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| receptors are densely expressed in nearly all cells that need to perform a function in response to an external cue |
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| at the subcellular level, receptors are present in several location. Receptors that are embedded in the lipid bilayer of the plasma memberane are called _________________. This type of receptor is also called a cell-surface receptor because part of the receptor protein is exposed to the extracellular fluid that is outside the membrane surface of the cell. Ligands or drugs are able to bind to transmembrane receptors without first becoming internalized by the cell. |
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| This type of receptor may be present in the cytoplasm or nucleus of the cell, or it may be associated with the membrane of an intracellular compartment. In order to bind to _____l ligands or drugs must first gain entrance to the cell through the plasma membrane. |
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| some receptors are soluble, meaning that they move freely about the body in blood and other extracellular fluids |
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| endogenous ligands and examples |
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Definition
| originate within the body, tissue, or cell ex. epinephrine, norepinephrine, dopamine, insulin, glucagon, erythropoietin, growth hormone, interleukins, interferons, hydrocortisone, estrogens, testosterone |
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| exogenous ligands and examples |
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| originate outside the body, tissue or cell ex. albuterol can bind to the active site of beta receptors in place of the endogenous ligand norepinephrine |
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| ligand-receptor competitive binding |
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Definition
| drugs may either bind to the endogenous ligand-binding site of a receptor or to another binding site. If the drug binds to tha ctive site of a receptor ane xcludes the engogenous ligand from binding then the nature of binding is said to be this. |
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| ligand receptor noncompetitive binding |
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Definition
| the binding of a drug to a receptor occurs independent of the endogenous ligand. allosteric binding is an example of this. irreversible binding appears to be this as well. |
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| drug-enzyme competitive inhibitors |
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Definition
| the drug blocks substrate access to the active site. resemble the structure of the endogenous substrate and bind reversibly to the active site of the enzyme. When the concentration of the drug is significantly higher than the concentration fo the substrate, the drug will effectively compete for access to thea ctive site. As a result, the substrate will be excluded from binding the th exyme and the reaction will not progress efficiently. This will shift the direct plot of the reaction velocity resulting in an increase in Km however, the Vmax of the reaction will not change. |
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| noncompetitive inhibitors (drug-enzyme) |
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Definition
| the drug binds to an alternate site and perturbs the ability of the enzyme to lower the activation energy of the reaction. They bind to a site on the enzyme that is different from thea ctive site. The effectiveness of the drug des not depend on substrate concentrations. Binding of a noncompetitive inhibitor forces the enzyme into a confromation that is inactive or unable to perfomr the chemical catalysis necessary for the reaction to progress. Noete that irreversible binding of an inhibitor to an enzyme, even if the inhibitor binds in the active site, will appear to be noncompetitive because no additional amount of substrate will be able to restore the normal activity of the enzyme. They change the apparent Vmax of the enzyme but will not affect Km. |
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| Describe the difference between reversible and irreversible drug-receptor binding and predict effects on the duration of drug action. |
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Definition
When a ligand binds to a receptor protein, the binding may either be reversible
or irreversible, depending on the chemical nature of the binding interaction Most drugs bind to receptors only temporarily and then become released, free to interact with another receptor or re-bind to the same receptor. With reversible binding, the receptor occupancy, or the number of
receptors bound to a ligand at any given time, is dependent upon the concentration of the ligand. If the ligand concentration is high, more binding sites are engaged in an interaction with a ligand. If the ligand concentration is low, only a few receptors will be occupied. This partially explains why the strength of the effect of most drugs is dependent on the dose of the drug: with a high drug dose more receptors will be occupied and a greater drug effect will occur. If a ligand binds to a receptor and a covalent bond is formed between the two then it is irreversible for the life of the receptor. The receptor occupancy depends not only upon the concentration of the ligand but also upon the amount of time that has elapsed. |
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| Describe three observations that support the receptor concept of drug action. |
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Definition
1. Receptor affinity determines the dose of a drug needed to produce a
pharmacologic effect, and the number of receptors defines the maximal
effect.
2. Receptors determine the selectivity of a drug.
3. Receptors mediate the pharmacologic actions of a drug as an agonist or
antagonist. |
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| Explain the clinical relevance of drug-receptor binding affinity and the selectivity of a drug for a receptor. |
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Definition
Affinity is a measure that describes the natural tendency for molecules to come together in a physical interaction. A drug molecule that has a high affinity for a receptor is likely to bind to the protein. Conversely, a drug that has a low affinity for a receptor is unlikely to bind to the protein. Another way to think about this in the context of reversible binding is that a ligand with high affinity for a receptor will spend more time interacting with the receptor before it becomes released.
Due to the diversity of proteins in our bodies, the number of potential receptors for any given drug molecule is huge. It is unlikely that a drug delivered into the body will bind to a single type of receptor. Drugs are useful in clinical medicine only if they bind preferentially to one or a few types of receptor and produce a distinct physiological effect. The term selectivity refers to how well a drug or endogenous ligand discriminates among different receptors and regulates discrete biochemical functions in the body. Selectivity can be measured by comparing the binding affinities of a drug between receptors of different types (usually expressed as a ratio) or by comparing the doses of a drug that are required to produce different effects. From the perspective of clinical medicine, selectivity is considered by separating therapeutic effects and toxic effects. A highly selective drug is one which produces a small number of predictable physiologic responses by interacting with a small set of receptors. Most drugs, however, are only
marginally selective. For example, the therapeutic effects of diphenhydramine (Benadryl®) to reduce an allergic response are due to its ability to bind histamine receptors. The drug also
binds to and inhibits cholinergic receptors, causing adverse effects like dry mouth and constipation. |
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| Provide definitions for Kd that relate to the rate of drug-receptor binding and the extent of receptor saturation. |
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Definition
The more common way to express affinity of a drug for a receptor is using the dissociation constant, or Kd. This number represents the ease with which a drug dissociates from the receptor binding site, or in other words, the constant describes the rate (k-1) for the reverse
of the binding reaction. The larger the number, the easier it is for a drug to leave the receptor site, and accordingly, the lower affinity the drug has for receptor binding. Therefore, drugs with a low Kd value have a high affinity for binding to a receptor. |
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| When given the value of Kd for two or more drugs, determine which drug has the higher or lower binding affinity for a receptor. |
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Definition
| Drugs with a low Kd value have a high affinity for binding to a receptor. |
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| Name the four categories of receptor signaling systems and provide examples of each |
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Definition
-G Protein-Coupled Receptors (GPCRs) - opioid receptors in the brain and adrenergic receptors in blood vessels, muscarinic acetylcholine receptors
-Ion-channel receptors - nicotine acetylcholine receptor, seratonin receptor subtype 5-HT
-Receptor Tyrosine Kinases - receptors for insulin, and for EFG (epidermal growth factor)
-Nuclear Receptors - receptors for steroidal drugs (dex,pred), Human androgen receptor |
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Term
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Definition
Activates G proteins by binding to an agonist then undergoes a conformational change that allows them to stimulate G proteins to release guanosine diphosphate (GDP) and bind to guanosine triphosphate (GTP). In the GTP bound form, G proteins are active and can stimulate effector enzymes. After activation the G protein hydrolyzes GTP and releases inorganic phosphate , returning to the inactive GDP.
There are many different effectors that respond to G proteins. In general, the G protein effectors produce a second messenger that continues the signal initiated by the GPCR.
ie enzyme phospholipase C (PLC) is activated by a G protein. PLC then produces a small molecule inosital triphosphate (IP). It is this molecule that travels thru the cytoplasm of cells and binds to secondary receptors that release calcium ions. |
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Definition
Ion channels are gated (receptor protein can open or close the channel in response to stimuli)
Ligand gated channels may open in response to the binding of endogenous agonist to the active site.
Voltage gated channels- open in response to changes in the membrane potential.
-some channels (ie voltage gated sodium channels) can be inactivated quickly after opening by a conformational change.
-After stimulation by changes in membrane polarity, it takes time for the resting potential to be restored. This is the refractory period and during this time the channel is closed, cannot be stimulated to open and is desensitized to agonist activation. |
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Definition
RTK are regulatory receptors as well as enzymes. The intracellular portion of these receptors forms and enzyme called Kinase. Kinase facilitates the transfer of a single phosphate from adenosine triphosphate (ATP) to a tyrosine amino acid residue of a target protein.
-After activation RTK can attach phosphates to themselves (autophosphorylation). the phosphate has a drastic effect on the conformation of the protein and may alter its activity, introduce new sites for interactions with other proteins or block intra or intermolecular binding sites.
-Drugs that inhibit RTK do not target the binding pocket on the extracellular domain of the receptor. Instead the drugs inactivate the tyrosine kinase domain. |
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Definition
| Nuclear receptors are intracellular receptors and need ligands or drugs that are lipophilic in order to cross the cell membrane. Steroidal drugs are ligands for intracellular steroid receptors. Once inside, the steroidal drugs bind with the steroid receptors. The receptors are then able to release chaperone proteins like heat shock protein-90 that interferes with the DNA-binding region of the receptors. After the chaperone protein has dissociated initially the receptor is free to bind with DNA which results in an altered gene transcription which will lead to a biological effect. |
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| Receptor desensitization: |
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Definition
With repeated administration, the effect of an agonist on target receptors may begin to diminish even though the dose remains the same. Example of this concept is the opioid agonist morphine, which is used to control pain. With repeated dosing, tolerance to morphine occurs and requires a dose increase to produce the same amount of pain
control. When tolerance to a drug occurs as a result of a decreased receptor response, it is called receptor desensitization. There are several ways in which receptors may become desensitized, including internalization (i.e., endocytosis) or reversible covalent modification
(e.g., phosphorylation) of receptors. Desensitization of a receptor that does not involve internalization of the receptor protein is also referred to as tachyphylaxis. Receptor desensitization is the body’s temporary defence against prolonged or excessive receptor activation. |
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Definition
When a receptor undergoes prolonged inhibition by an antagonist, cells may adapt by increasing the surface density of the receptor.This process is called receptor up-regulation and it involves several steps including transcription of the receptor gene, synthesis of the protein, and transport of the new receptor proteins to the surface of the plasma membrane (or cytoplasm, in the case of intracellular receptors).
Whereas desensitization or down-regulation results in a diminished physiological response to the presence of receptor agonists, upregulation promotes greater sensitivity to drugs or endogenous ligands that activate a receptor signaling pathway |
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| Receptor down-regulation: |
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Definition
The concept of receptor down-regulation applies to membrane-bound receptors that have been internalized. When receptors are internalized into the cell via endocytosis, they are unable to bind with drugs or ligands that remain outside of the cell. Note that the possible fates of internalized receptors include storage, recycling to the plasma membrane or degradation. Down-regulation occurs if these receptors are hydrolyzed within the lysosome, an intracellular organelle responsible for degrading proteins and other unwanted materials. Following withdrawal of the drug agonist, new receptors gradually replace the down-regulated receptors and the original density of receptors is restored. In other words, neither desensitization nor down-regulation is permanent.
Desensitization and down-regulation of receptors are adaptive changes to the presence of a ligand. Both have been used to explain drug phenomena such as drug tolerance and withdrawal symptoms. |
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| Ligand gated ion channels |
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Definition
| Comformational changes in the receptor protein can open or close the channel in response to different stimuli. Ligcanggated ion channels, like the nicotinic acertylcholine receptor may open in response to the binding of an endogenous agonist to the active site on the extracellular portion of the protein. |
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Term
| voltage gated ion channels |
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Definition
| open in response to changes in the membrane potential .Because the concentrations of positve and negative ions on the inside and outisde of cells are not equivalent, there is a charge difference across the plasma membrane. voltage gated ion channels respond to changes in this charge difference to allow ions to flow across the membrane. Although voltage gated ion channels do not have endogenous ligands, they are nenbertheless important targets for drugs. |
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| regulation of ion channels |
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Definition
| to stop the transmission of ions across the membrane, some hannels can be inactivated fairly quickly after opening by confromational change. over time these channels return to their normal shape and regain the ability to open in response to chagne sin membrane voltage. Following the stimulation of voltage gated channels by changes in membrane polarity it may take time for the resting potential of the membrane to be restored. |
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| locations of ion channel receptors |
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Definition
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| Discuss the activation and deactivation cycle of G proteins. |
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Definition
| G proteins are bound to a small molecule called a nucleotide that can exist as a mono-, di-, or tri-phosphate. The state of the guanine nucleotide acts as a switch that turns the G protein on or off. Upon binding to an agonist, GPCRs undergo a conformational change that allows them to stimulate G proteins to release guanosine diphosphate (GDP) and bind guanosine triphosphate (GTP). In the GTP-bound form, G proteins are active and can stimulate effector enzymes. Shortly after activation, the G protein hydrolyzes GTP and releases inorganic phosphate, returning to the inactive GDP-bound form. |
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Definition
Norephinephrine/epinephrine
Autonomic drugs
Alpha adrenergic agonist
Alpha adrenergic antagonists
Beta adrenergic agonists
Beta adrenergic antagonists |
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Definition
acetylcholine
Autonomic Drugs
Cholinergic agents
Cholinergic antagonists (anticholinergic)
Neuromuscular blockers |
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dopamine
dopamine agonists
dopamine antagonists |
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serotonin
serotonin agonists
serotonin antagonists |
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endorphins
opioid agonists and antagonists |
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| Discuss mechanisms for how enzymes alter the rates of chemical reactions. |
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Definition
| Enzymes lower the activation energy needed to start a chemical reaction. This means that the enzyme increases the rate of the reaction, BUT it does not increase the concentration. Just strictly the rate. |
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| Distinguish between coenzymes and prosthetic groups and explain why cofactors are needed for certain enzyme reactions. |
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Definition
Coenzymes are held loosely by the enzyme and may be released relatively easily. Examples of this type of cofactor include the reducing agent nicotinamide-adenine-dinucleotide (NADH) used
during cellular respiration and the conversion of fats and carbohydrates into energy, and the metal ions used by polymerase to replicate DNA during cell division. Prosthetic groups are tightly (often covalently) bound cofactors, which include the heme groups found in the cytochrome enzymes that metabolize drugs in the liver. |
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Term
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Definition
Oxidizes substrates by transferring an electron (or hydride,
H- ion) to an electron accepting cofactor (e.g., NAD+). ex: any of the dehydrogenase enzymes - acetaldehyde dehydrogenase (ALDH). Drug that inhibits this enzyme: Antabuse |
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Definition
| mechanism of intracellular signaling when the enzymatic transfer of a phosphate group (PO4 2-) from adenosine triphosphate (ATP) to specific amino acid residues on a protein ex: Kinases. Drugs that inhibits this enzyme: Tarceva, Gleevec |
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Definition
| All hydrolases split larger molecules into smaller ones, using a molecule of water in the process.ex: Phospholipase C, lactase, esterase enzymes Drugs that inhibit esterases (well cholinesterase in this instance): pyridostigamine, neostigmine <<- not sure about these drugs |
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| six general types of reactions catalyzed by enzymes |
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Definition
| oxidoreductase, transferases, hydrolase, lyases, isomerases, ligases |
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Definition
| aprotein in a signalling pathway that is activated by a regulator receptor and mediates ar esponse |
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Definition
| the three dimensional shape of a protein |
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Definition
| the natural tendency for objects to interact |
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Definition
| the point at which all available receptors are occupied by a ligand |
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Definition
| the rate of reaction; the conversion of substrate to product over time |
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Definition
| with a given amount of enzyme, the fastest rate of product formation occurs when the substrate is abundant |
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Definition
| Michaelis constant is used to describe the concentration of substrate necessary to achieve half of maximal velocity. |
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