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Drug Target - Receptors

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allelipraise's version from 2017-10-23 21:59

Section 2

Question Answer
CNSSends message to the nerves with the use of electrical Pulse
NervesSends Chemical Messengers to the Target Site
TargetMuscle/ Neuron
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Section 3

Question Answer
ReceptorsFunctional macromolecular cell component with specific stereochemical configuration with which a ligand interacts
Chemical MessengerBring about cell responses
Chemical Messenger Do not undergo reaction when bound to the receptor
Signal TransductionProcess by which incoming signals are conveyed to the target cell’s interior
CM-Receptor binding interactionStrong enough to cause biological effects
CM-Receptor binding interactionWeak enough to be removed
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Section 4

Question Answer
ReceptorsBiological macromolecule that yields biological response upon interaction with a drug molecule
John LangleyReceptors are first conceptualize by?
Paul EhrlichReceptors are term is introduced by?
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Section 5

Question Answer
Lock and Key TheoryPostulated by Emil Fischer (1894)
Lock and Key Theory Complementarity between substrate and its binding site is rigid
Lock and Key TheoryUseful for visualizing how the enzyme-substrate complex is formed
Occupancy TheoryPostulated by Clark and Gaddun (1926)
Occupancy TheoryOne drug molecule occupies one receptor site
Occupancy TheoryDependent on the # of receptors occupied
Occupancy TheoryIntensity of pharmacological effect is directly proportional to number of receptors occupied
Occupancy Theory↑ occupied receptors = ↑ response
Occupancy Theory=saturation kinetics Point in which all receptors are occupied, any addition of drug does not intensify the effect
Occupancy TheoryApplicable when the drug-receptor interaction is the same for all the drugs being considered in a series
Occupancy TheoryLoopholes=With a certain series of drugs, a maximal dose response was never achieved
Occupancy TheoryLoopholes=Biological effect does not always appear to follow law of mass action
Occupancy TheoryLoopholes=Is not dependent on the drug affinity for the receptors
Modified OccupancyAriens and Stephenson
2 step phenomenon in Drug-Receptor InteractionComplexation of drug with receptor
2 step phenomenon in Drug-Receptor InteractionProduction of effect
Modified OccupancyAffinity with receptor is not sufficient, compound must have intrinsic activity
Modified Occupancy=intrinsic activityDescribes the ability of drug-receptor complex to produce biological effects
Modified OccupancyLoophole=Fails to explain how drugs vary in their action
Modified OccupancyLoophole=Difference between the activity of agonists and antagonists
Modified OccupancyLoophole=Does not suggest mechanism of action on the molecular level
Induced-Fit TheoryDaniel E. Koshland Jr. (1958)
Induced-Fit TheoryBiological effect is caused by induction of proper conformational change
Rate TheoryDrug is effective only at a moment of encounter with its receptor
Rate TheoryReceptor activation is proportional to the total number of encounters of the drug with its receptors per unit time
Rate Theory No stable drug-receptor complex
Rate Theorythe duration of receptor occupation determines whether a molecule is agonist, partial agonist or antagonist
Rate TheoryLoopholes = Agonists form relatively stable complexes
Rate TheoryLoopholes =Drug phenomena on molecular level cannot be explained
Rate TheoryLoopholes =Cannot explain the difference in action of two similar compounds that are antagonistic to each other
Macromolecular Perturbation TheoryProposed by Belleau
Macromolecular Perturbation TheorySuggests that when a drug-receptor interaction occurs, one of two general types of ______________ is possible
specific conformational perturbation leads to a biological response (agonist)
non specific conformational perturbationleads to no biologic response (antagonist)
Activation-Aggregation TheoryProposed by Changeux
Activation-Aggregation TheoryReceptors have inherent activity
Activation-Aggregation TheorySuggests that receptors do not have fixed conformation
Activation-Aggregation TheoryReceptors continually change shape until an equilibrium is established between the 2 states, active conformation and inactive conformation
Activation-Aggregation TheorySuggests that a drug receptor (in the absence of a drug) still exists in an equilibrium between an activated state (Bioactive) and an inactivated state (Bio-inactive)
Activation-Aggregation Theory=agonistbind to the activated state
Activation-Aggregation Theory=antagonistbind to the inactivated state
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Receptor

Question Answer
Cell MembraneReceptor Location
IntracellularReceptor Location
Nuclear MembraneReceptor Location
Each cell has range of receptorsReceptor Distribution w/in the cell
the cell membrane making it responsive to different chemicalsReceptor Distribution w/in the cell
SpecificityReceptor Structure
Binding SiteReceptor Structure
Message TransmissionReceptor Function
Message ReceptionReceptor Function
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Section 6

Question Answer
Type I ReceptorsIonotropic Receptor
Ionotropic Receptor Onset: Rapid (milliseconds)
Voltage-gated Ion Channelsclass of transmembrane ion channels that are activated by changes in electrical membrane potential near the channel
(Na,K) open and close in response to stimuli, gating the flow of specific small ions
Voltage-gated Ion Channels Signal transmission along individual neurons
Voltage-gated Ion ChannelsUsed for Anaesthetics
Ligand-gated Ion ChannelsWhen a ligand binds to this type of receptor, the channel changes conformation such that it is more or less permeable to one or more ions.
Ligandsendogenous substances, neurotransmitters ( GABA, Ach)
Ion channels5 protein sub-units lined with amino acids to give a hydrophilic pore
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Section 7

Question Answer
Type II ReceptorsMetabotropic receptors
Metabotropic receptorsOnset: seconds
Metabotropic receptors7 transmembrane spanning receptors which ↑ or ↓ secondary messengers → signal transduction
Type II ReceptorsG-Protein Coupled Receptor
G-Protein Coupled ReceptorGenerally activated by hormones and slow-acting neurotransmitters
Muscarinic, adrenergic, opioidHormones and Neurotransmitter of G-Protein
activate G-proteinswhich are capable of activating or deactivating membrane bound enzymes which consequently, activates the receptor by a chemical messenger and influences reactions within the cell
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Section 8

Question Answer
Kinase-linked ReceptorsActivate enzymes directly (do not require a G-protein)
Kinase-linked ReceptorsTyrosine kinase receptor
Activated by polypeptide hormones, growth factors, cytokinesKinase-Linked Receptors are activated by?
Kinase-linked Receptors: DependentAmplification of the signal is __________ on the duration of the binding
Type III ReceptorsKinase-linked Receptors
Phosphorylation Reaction ATP to AMP Reaction of Kinase Linked Receptor
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Section 9

Question Answer
Type IV ReceptorsGene Transcription-linked Receptors
Nuclear
Receptor
Gene Transcription-linked Receptors Another name?
modulating gene transcriptionGene Transcription-linked Receptors is responsible for?
Gene Transcription-linked ReceptorsLocated in the nucleus
Gene Transcription-linked ReceptorsOnset: hours
• Steroid receptors • Thyroid hormone receptorsGene Transcription-linked Receptors(CM)?
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Section 10

Question Answer
Chemical MessengersActivate receptors without undergoing a reaction/ change
Chemical Messengers– Neurotransmitters – Hormones – Paracrines – Neurohormones
HormonesSecreted into blood by endocrine glands in response to appropriate signal
Hormones Travel long distances through the blood supply
HormonesExert effect on target cells some distance away from release site
HormonesNonpolar • (Adrenaline)
NeurotransmittersDiffuse across narrow space to act locally on adjoining target cell (another neuron, a muscle, or a gland)
Neurotransmitters Travel short distances – cell to cell
NeurotransmittersPolar
MonoaminesACh, NA, dopamine, 5-HT
Amino acids GABA, glutamic acid, glycine
ParacrinesExert effect only on neighboring cells in immediate environment of secretion site
ParacrinesLocal chemical messengers
NeurohormonesHormones released into blood by neurosecretory neurons
Neurohormones Distributed through blood to distant target cells
neurosecretory neuronsHormones released into blood by?
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Section 11

Question Answer
AgonistsHave the same biological activity as endogenous chemical messengers
AgonistsMimic the natural messengers
AgonistsHave similar structure
AgonistsForm similar intermolecular bonds
AgonistsSame manner of alteration of receptor conformation
AgonistsActivates receptors
AntagonistsBlocks original messenger
AntagonistsDifferent/ opposite effect
AntagonistsNo intrinsic activity
Competitive InhibitionBinding results in inactivation of receptor
Competitive InhibitionNo inherent activity
Competitive InhibitionReversible
Competitive Inhibition↑ conc of CM will reverse antagonism
Competitive InhibitionDegree of antagonism
Competitive InhibitionStrength of antagonist binding
Competitive InhibitionConcentration
Allosteric InhibitionNon-competitive inhibition
Allosteric Inhibition Binds to a different site (allosteric site) → change in conformation of R → unrecognizable R
Allosteric InhibitionAn ↑ conc of CM will not reverse antagonism
Umbrella EffectBinds reversibly to a neighboring binding site which overlap with the messenger binding site
Umbrella EffectMessenger is blocked from the binding site
Partial AgonistBinding causes a conformational change that results to insufficient activation
Partial AgonistActivation and inactivation
Partial AgonistThe conformational change (by the receptor) induced is not ideal and the subsequent effects of receptor activation are decreased.
Partial Agonistcapable of binding to a receptor in two different ways by using different binding regions in the binding site.
Partial Agonist Receptors that bind the same chemical messenger are not all the same.
Inverse AgonistsNegative antagonists
Inverse AgonistsAct on the same receptor as the agonist but exerts opposite effect
Inverse AgonistsHas the same effect as an antagonist
Inverse Agonists– Fail to activate receptor
Inverse Agonists– Prevents binding of the endogenous CM
Inverse Agonists– Allosteric antagonist
Inverse Agonists– Prevents inherent (constitutional) activity of receptors (eg. GABA, dihydropyridine, serotonin)
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Section 12

Question Answer
Active conformationBinding Preference=Agonist
Active and inactive conformationBinding Preference=Antagonist
Slight preference for the active over any of the inactive conformationBinding Preference=Partial Agonist
Inactive conformationBinding Preference=Inverse Agonist
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Section 13

Question Answer
Receptor Internalization Tolerance • Dependence • Withdrawal Symptoms
ToleranceLoss of response to the usual given dose
ToleranceHigher levels of drug are required to get the same biological response
DependenceA certain drug that had been stopped and had to be taken again in order to prevent withdrawal symptoms
Withdrawal SymptomsThe cell became supersensitive to neurotransmitters as a result of over production of receptors
Withdrawal SymptomsA result of stopping the drug abruptly after prolonged period of taking
Sensitizationan alteration of responsiveness of the body to the presence of foreign substances.
Desensitizationreducing the effects of a known allergen by injecting, over a period, gradually increasing doses of the allergen until resistance is built up.
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