Pharmacological Glossary

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Definitions of commonly used pharmacological terms

Absorbance:

Absorbance is used for assays such as ELISA assays, protein and nucleic acid quantification or enzyme activity assays (i.e. in the MTT assay for cell viability). A light source illuminates the sample using a specific wavelength (selected by an optical filter, or a monochromator), and a light detector located on the other side of the well measures how much of the initial (100 %) light is transmitted through the sample: the amount of transmitted light will typically be related to the concentration of the molecule of interest.

ADME:

An acronym in pharmacokinetics and pharmacology for absorption, distribution, metabolism, and excretion, and describes the disposition of a pharmaceutical compound within an organism.

Agonist:

A drug capable of binding and activating a receptor, leading to a pharmacological response that may mimic that of a naturally occurring substance. It can be classified as full, partial or inverse.

Full agonist:

Capable of eliciting a maximal response as it displays full efficacy at that receptor.

Partial agonist:

Binds to and activates a receptor but is only able to elicit partial efficacy at that receptor. A maximal effect cannot be produced, even when the concentration is increased. When full and partial agonists are present the partial agonist may act as a competitive antagonist.

Inverse agonist:

Produces an effect that is pharmacologically opposite to an agonist, yet acts at the same receptor. The receptor must elicit intrinsic or basal activity in the absence of a ligand and the addition of an inverse agonist will decrease the activity below the basal level. A receptor that possesses basal activity is the GABAA receptor; agonists have a sedative effect whilst inverse agonists have an anxiogenic effect.

Antagonist:

Does not produce a biological response on binding to a receptor but instead blocks or reduces the effect of an agonist. It may be competitive or non-competitive.

Competitive antagonism:

Drug binds selectively to a receptor without causing activation but in such a way to prevent binding of the agonist. The antagonism may be reversible; the effect can be overcome by increasing the concentration of the agonist, which will lead to a shift in the equilibrium.

Non-competitive antagonism:

A non-competitive antagonist may affect the reaction by binding to the active site of the receptor or to an allosteric site, therefore not competing with the agonist. The magnitude of the maximal response is reduced, regardless of the amount of agonist present.

Allosteric modulator:

A drug that binds to a receptor at a site distinct from the active site. A conformational change is induced in the receptor, altering the affinity of the receptor for the endogenous ligand.

Positive allosteric modulators:

Increase the affinity of the receptor for the endogenous ligand.

Negative allosteric modulators:

Decrease the affinity of the receptor for the endogenous ligand.

AUC:

The area under the plasma (serum, or blood) concentration versus time curve. It is used in toxicology, biopharmaceutics and pharmacokinetics.

Bmax:

Maximum amount of drug which can bind specifically to receptors in a membrane preparation. If one drug molecule binds to each receptor it acts as an indication of the concentration of receptors in the tissue.

Cheng-Prusoff equation:

Used to determine the Ki value from an IC50 value.



Where [L] is the concentration of free radioligand, and Kd is the dissociation constant of the radioligand for the receptor.

Desensitization:

A loss of responsiveness which may be due to the continued presence of an agonist at a receptor or repeated presentation of the agonist

EC50:

The molar concentration of an agonist that produces a 50% response of the maximum possible response for that agonist. Figures may also be stated as other percentages of the maximum response EC20 and EC80 representing a 20% and 80% response respectively.

ED50:

Dose of drug that produces 50% of its maximum response or effect. Can be a term used in vitro or in vivo (although it is more common in vivo).

Efficacy:

Used to describe agonist responses in relation to receptor occupation. High efficacy agonists can produce a maximal response whilst occupying a relatively low proportion of receptors. Low efficacy agonists are unable to cause receptor activation to the same degree and a maximal response may not be achieved even at full occupation of the entire receptor population. Low efficacy agonists are often termed partial agonist.

ELISA:

Enzyme-linked immunosorbent assay, also known as an enzyme immunoassay (EIA), is a biochemical technique used mainly in immunology to detect the presence of an antibody or an antigen in a sample.

Ex vivo:

Experimentation using tissue in an artificial environment outside the living organism. An example may include short-term (up to 24 hour) culture of tissue, following its removal from the organism.

Half-life (t1/2):

An important pharmacokinetic measurement. The metabolic half-life of a drug in vivo is the time taken for its concentration in plasma to decline to half its original level. t1/2 refers to the duration of action of a drug and depends upon how quickly the drug is eliminated from the plasma. Clearance and distribution of a drug from the plasma are important parameters for half-life determination.

Fluorescence:

A first optical system (excitation system) illuminates the sample using a specific wavelength (selected by an optical filter, or a monochromator). As a result of the illumination, the sample emits light (it fluoresces) and a second optical system (emission system) collects the emitted light, separates it from the excitation light (using a filter or monochromator system), and measures the signal using a light detector such as a photomultiplier tube (PMT). The advantages of fluorescence detection over absorbance detection are sensitivity, as well as application range, given the wide selection of fluorescent labels available today.

Fluorescence polarization:

The samples in the microplate are excited using polarized light (instead of non-polarized light in FI and TRF modes). Depending on the mobility of the fluorescent molecules found in the wells, the light emitted will either be polarized or not.

Hit:

A chemical compound that produces a result in a preliminary biochemical test indicating that the compound merits further study as part of a drug discovery project.

IC50:

Molar concentration of an agonist or antagonist that causes 50% of the maximum possible inhibition. Figures may also be stated as other percentages of the inhibition.

ID50:

In vitro or in vivo dose of a drug that causes 50% of the maximum possible inhibition for that drug.

In vitro:

Studies carried out using components of an organism that have been isolated from their usual biological surroundings. The analysis is usually carried out in test-tubes or culture dishes.

In vivo:

Experimentation using the whole living organism. Normal physiology will be involved in any response.

KA:

Equilibrium dissociation constant for an agonist; the concentration at which 50% of receptors would be occupied at equilibrium.

KB:

The equilibrium dissociation constant for a competitive antagonist; the concentration at which 50% of the receptors would be occupied at equilibrium.

Kd:

The dissociation constant. Concentration of a drug which at equilibrium occupies 50% of receptors.

Ki:

Inhibition constant for a drug where 50% of receptors will be occupied. Provides an absolute value and does not differ between experiments. Calculated from the IC50 value using the Cheng-Prusoff equation.

Lead compound:

(1) a compound that has been selected from a group of hit compounds based on qualities such as the intensity of the biochemical effect that occurs when the compound is present (efficacy), or the absence of coincidental effects (specificity);
(2) a chemical compound that has pharmacological or biological activity and whose chemical structure is used as a starting point for chemical modifications in order to improve potency, selectivity, or pharmacokinetic parameters.

Luminescence:

The difference with fluorescence is that the light emitted by the samples is the result of a chemical or biochemical reaction (instead of being the result of excitation by light). Luminescence plate readers are simpler optically than fluorescence readers, as they don't require a light source, just a light detector. Typically, the optical system consists in a light-tight reading chamber, and PMT detector measuring the light emitted by the samples during the reaction. Common applications include luciferase-based gene expression assays, as well as cell viability and cytotoxicity assays based on the luminescent detection of ATP.

Non-specific binding:

Proportion of radioligand that is not displaced by other competitive ligands that are specific for a particular receptor. It can be due to: Binding to other receptors or proteins; Partitioning into lipids.

pD2:

Negative logarithm of the EC50 or IC50 value.

pEC50:

Negative logarithm of the EC50 value.

pIC50:

Negative logarithm of the IC50 value.

pKA:

Negative logarithmic measure of the potency of an antagonist.

pKB:

Negative logarithm of KB value. For a competitive antagonist the pKB theoretically equals the pA2 value.

pKd:

Negative logarithm of the Kd value.

pKi:

Negative logarithm of the Ki value.

Potency:

Measure of the effective concentration of a drug. It is a vague term and it is advisable to further categorise the measurement:
Agonists – EC50, IC50 or pD2
Antagonists – pA2, KB or pKB

Occupancy:

The proportion of receptors to which a drug is bound.



[D] = Drug concentration K = Dissociation constant

Specific Binding:

The proportion of radioligand that can be displaced by competitive ligands specific for the receptor. t1/2 The biological half-life of a drug or radioligand in vitro or in vivo. In vitro, the t1/2 of the effect of a drug is the time taken for the response to a drug to decline to half the original response. In radioligand binding, the t1/2 can be used to measure the dissociation rate of a radioligand from its receptor, therefore it is the time taken for the amount of radioligand bound to the receptors to decline to half its original level. In vivo, t1/2 refers to the metabolic half-life of a drug or radioligand, i.e. the time taken for the concentration of a drug in plasma to decline to half its original level.

Time-of-flight mass spectrometry (TOFMS):

Time-of-flight mass spectrometry (TOFMS) is a method of mass spectrometry in which ions are accelerated by an electric field of known strength. This acceleration results in an ion having the same kinetic energy as any other ion that has the same charge. The velocity of the ion depends on the mass-to-charge ratio. The time that it subsequently takes for the particle to reach a detector at a known distance is measured. This time will depend on the mass-to-charge ratio of the particle (heavier particles reach lower speeds). From this time and the known experimental parameters one can find the mass-to-charge ratio of the ion.

Time-resolved fluorescence (TRF):

Relies on the use of very specific fluorescent molecules, called lanthanides, that have the unusual property of emitting over long periods of time (measured is milliseconds) after excitation, when most standard fluorescent dyes (e.g. fluorescein) emit within a few nanoseconds of being excited. As a result, it is possible to excite lanthanides using a pulsed light source (Xenon flash lamp or pulsed laser for example), and measure after the excitation pulse. This results in lower measurement backgrounds than in standard FI assays.

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