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16 Cards in this Set
- Front
- Back
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Whatare the Major Targets of Drugs? |
-Enzyme -Transporters -ion channels -receptors |
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Whatis a Receptor? |
Receptorsare target molecules through which soluble physiological mediators can producetheir desired biological effects |
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DifferentTypes of Receptor |
Ligand-GatedIon Channels G Protein-Coupled Receptors Enzyme-CoupledReceptors NuclearReceptors |
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Whatis a G Protein-Coupled Receptor? |
•Seventransmembranedomains •Coupleto G proteins to initiate signal transduction •Activatedby diverse signals: Photons, hormones, peptides, peptidases •Olfactoryand Non-olfactory |
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Whyare G Protein-Coupled ReceptorsImportant? |
•GPCRscurrently represent more than half the current drug targets ➟stomachulcers e.g., Ranitidine, histaminereceptors ➟allergies e.g., Loratidine,histamine receptors ➟nausea e.g., Metoclopramide, dopamine receptors ➟hypertension e.g., Atenolol, b-adrenoceptors ➟migraines e.g., Sumatriptan,5-HT receptors ➟glaucoma e.g., Pilocarpine,muscarinicACh receptorsGPCRClassification |
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GPCRClassification |
Sixclasses based on sequence homology and functional similarity Class A: Rhodopsin-like Class B: Secretin-like Class C: Metabotropicglutamate/pheromone ClassD: Fungalpheromone ClassE: cAMPreceptors ClassF: Frizzled/Smoothened |
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ClassA: Rhodopsin-like |
➟namedafter the prototypical GPCR: Rhodopsin➟shortN-terminus ➟agonistsbind with extracellular loops and transmembranedomains ➟majorityof prescribed GPCR drugs target Class A ➟b-adrenoceptors,histamine receptors, dopamine receptors |
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ClassB: Secretin-like |
➟namedafter the prototypical GPCR: Secretin➟larger,globular N-terminus;plays role in agonist binding ➟currentlyno small molecule drugs on market ➟secretinreceptors, calcitonin receptors, glucagon receptors |
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ClassC: Metabotropicglutamate |
➟namedafter the prototypical GPCR: Metabotropic glutamate receptors ➟verylarge N-terminal domain binds agonists; form obligatory dimers ➟fewsmall molecule drugs on market ➟metabotropicglutamatereceptors,GABAB receptors |
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Howare GPCRs Activated? |
The agonist binds to GPCR which cause a conformational change which attracts Heterotrimeric G Protein formed alpha, beta, gamma. It is unfavourable for GDP to bind which activates GTPase activity which converts GDP to GTP. Beta and gamma dissociate form alpha + GTP and away form GPCR. Then signalling to effectors. |
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Ga (stimulatory) |
promotes activity of adenylate cyclase which converts ATP to cAMP which activates protein kinase A |
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Gai/o (inhibitory) |
inhibits adenylate cyclase; this prevents the conversion of ATP to cAMP -> deactivation of protein kinase A |
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Gaq/11 |
Docent act on adenylate cyclase. It recruits phospholipase C to the plasma membrane PIP2 is a substrate for phospholipase C. This is cleaved into two smaller fragments, one stays in the plasma membrane and the other smaller fragment IP3. These activate different signalling pathways. DAG activates protein kinase C recruits to plasma membrane. IP3 binds to receptors on ER causes efflux of Ca+ into cell. |
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Desensitisation |
1. Agonist bind to GPCR which cause conformational change 2. GRK attracted to GPCR and promotes phosphorylation on protein receptors 3. Phosphorylated form go GPCR attracts B arresting and bind to it 4. These recruit scaffolding proteins, forming cages around GPCR. 5. These facilitates internalisation of GPCR into intracellular vesicles-endosomes 6. Once in endosomes ligand released and so is arresting + the receptor become dephosphorylated 7. Then there are two fates either recycling back to cell surface or can be trafficked to where they are then degenerated -> Homologous desensitisation: effects are restricted to agonists acting through a specific receptor -> Heterologous desensitisation: effects can affect receptors that share a component of the same signalling cascade |
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Tolerance |
is the progressive reduction in the effectiveness of a drug: usually occurring over days or hours |
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Development of tolerance at u-opiod receptors |
-> endogenous agonist such as then enkephalins have an increase efficacy for endocytosis -> u-opiod receptors desensitise, internalise + recycle following activation by endogenous agonists -> agonists such as morphine have a low efficacy for endogenous (partially) -> u-opoid receptors desensitise, internalise poorly + recycle slowly following activation by morphine ->enkephalins + morphine activate unique sets of signalling pathways -> morphine is a 'partial' agonist |
