07: receptor pharmacology

receptor pharmacology

study of the interactions of receptors with drugs/pharmaceuticals and other xenobiotics (substances that are foreign to the body)

receptor

component of a cell that interacts with a specific ligand ad initiates the chain of events leading to the observed effect

neurotransmitters

released by neurons and affect other neurons or effector cells near the release site

ligand

molecule that binds to a receptor to send signals leading to a change in cell signalling/activities, and ultimately, cell behavior, or structure

intracellular ligands

ligands that bind to receptors inside the cell

extracellular ligands

ligands that bind to receptors outside the cell

cell surface receptors

typically trigger downstream cell signaling pathways

intracellular receptors

typically directly trigger downstream transcriptional activities of gene activation/inhibition

lock and key model

enzymes recognize their substrates as a lock receives a key

induced fit theory

substrate or ligand binding causes a subsequent conformational change in the complex

selectivity

refers to a drug’s strong preference for its intended target over other targets

specificity

describes the extent to which a drug produces only the desired therapeutic effect without causing any other physiological changes

ligand binding assays

directly capture the engagement and binding of ligand-receptor

functional assays

measure the actual biological response (electrical or biochemical or physical) evoked by the ligand via its receptor

dose

amount of drug administrated in the patient

response

effect shown by the body to a particular drug

fractional occupancy

fraction of all receptors that are bound to ligand

potency

concentration (EC50) or dose (ED50) of a drug required to produce 50% of that drug’s maximal effect

efficacy (E_max)

maximum effect which can be expected from this drug

slope

reflects the effect of incremental increase in doses vs. response

variability

reflects reproducibility/consistency of data, which can be variable between testing subjects

median effective dose (ED₅₀)

dose at which 50% of individuals exhibit the specified quantal effect

median lethal dose (LD₅₀)

dose required to kill 50% of subjects

median toxic dise (TD₅₀)

dose required to produce a defined toxic effect in 50% of the subjects

therapeutic index (TI)

numeric measure of the selectivity of the drug for its desired effect

therapeutic window

range between the minimum toxic dose and the minimum therapeutic dose

agonist

compound that binds to a receptor and produces the biological response

partial agonist

produces the biological response but cannot produce 100% of the biological response even at very high doses

antagonists

block or reverse the effect of agonists

competitive antagonist

• competes for the same site on the receptor that the agonist binds

• makes the agonist look less potent

non competitive antagonist

• reduces the maximal response that an agonist can produce

• decrease the apparent intrinsic activity of the agonist

inverse agonists

have opposite (or negative) effects from those of full agonists

cooperativity

manifested when the binding of a ligand to a protein alters the affinity for subsequent binding of the same ligand

allostery

observed when binding of a ligand changes the protein conformation, altering the availability/affinity to another binding site to a different ligand

allosteric modulators

drugs which can bind to a site distinct from the orthosteric site

orthosteric site

binding site of the endogenous or natural agonist

positive allosteric modulator X

shifts the EC50 for the agonist

leftward (i.e., increases the potency of the

agonist)

positive allosteric modulator Y

increases the Emax for the agonist

(i.e., increases efficacy)

negatove allosteric modulator

has a negative impact on both

EC50 and Emax, reducing potency and

efficacy