Molecular targets (receptors etc)

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Created by
kimch

Cards (60)

  • What are the %s of drugs that target major families:
    -Kinases -3%
    -Ion channels - 18%
    -Nuclear receptors -16%
    -GPCRs - 33%
  • What is the intracellular concentration of potassium?
    -150mM greater than extracellular potassium between 3-5 mmol
  • Potassium channels:

    -Most diverse family of ion channels.
    -More than 70 different genes encoding K channels α subunits in the human genome.
  • What is the function of potassium channels?
    Regulate cell excitability through different modalities:
    Frequency and shape of action potentials.
    Secretion of hormones and neurotransmitters.
    Membrane potential.
  • What is the function of Minoxidil?

    -Opens potassium channels
    -Causes hyperpolarisation in smooth muscle cells
    -Muscle relaxation and hence vasodilation.
    -Indication: Can be used in the treat of hypertension in combination with a diuretic and β adrenoreceptor blocker
    -Recent evidence states it can stimulate hair growth
  • Sodium channels:
    -The first members of the ion channel superfamily to be discovered.
    -Voltage-gated sodium-selective ion channels present in the membrane of most excitable cells.
    -Comprise of one pore-forming α subunit, which may be associated with either one or two β subunits.
    -Encoded by at least 10 genes.
    -nAChR, glutamate & 5HT3 are all excitatory receptors
  • What is lidocaine?

    Blocks voltage-gated sodium channels (Nav1.5, Nav1.7, Nav1.9).
    Primary target is Nav1.5 which is the main cardiac sodium channel.
    Indication: ventricular arrhythmias, especially after myocardial infarction. In addition to local anaesthesia.
  • Calcium channels:

    -Voltage-gated ion channels present in the membrane of most excitable cells.
    -Ca2+ channels form hetero-oligomeric complexes.
    -The α1 subunit is pore-forming and provides the extracellular binding site(s) for practically all agonists and antagonists.
    -Glycine and GABA receptors are inhibitory
  • What are the 3 calcium channel families?High-voltage activated dihydropyridine-sensitive (L-type, CaV1.x) channels; 2.High-voltage activated dihydropyridine-insensitive (CaV2.x) channels 3.Low-voltage-activated (T-type, CaV3.x) channels.
    -The α2-δ1 and α2-δ2 subunits bind gabapentin and pregabalin
  • What is verapamil?

    -Blocks L types voltage gated calcium channels
    -Blocks calcium influx in myocardial and vascular smooth muscle cells.
    -Leads to a reduction in cardiac and VSM contraction bringing about a dilation in coronary and systemic arteries.
    -Indication: supraventricular arrhythmias, angina, hypertension (dose and preparation dependent)
  • Sodium channel channelopathy:

    -Epilepsy
    -Pain
  • Potassium channels channelopathy:

    -Epilepsy
    -Diabetes
    -Ataxia
  • Calcium channels channelopathy:

    -Pain
    -Ataxia
    -Epilepsy
  • Potassium ATP channels channelopathy:
    -Diabetes
  • What are ligand gated ion channels?
    -Membrane proteins that contain a pore which allows regulated flow of selected ions across plasma membrane
    -Link ligand binding to an ionic flux
    -Ion flux is passive and driven by electrochemical gradient
    -Heteromeric assemblies with 4-5 subunits.
    -Mediate fast synaptic transmission in milliseconds in CNS and somatic NMJ
    -Nicotinic ACh receptor first to be cloned.
  • Acetylcholine receptors

    -Nicotinic
    -Structure solved by X-ray crystallography
    -Each subunit has 4 transmembrane (TM) domains
    -TM2 from each subunit lines the ion channel pore
    -Sodium flows along its concentration gradient
    -Causes depolarisation of cell
    -In muscle
    = contraction
    -In neurons = increases probability of neurone firing action potential
    -Action is FAST, within milliseconds of ligand binding
    -Different nAChRs exist, depending on which subunits are assembled into the complex:
    -(a1)2b1dγ = muscle subtype
    -(a4)2(b2)3 = one of the CNS subtypes
  • What is Succinylcholine?

    -Full agonist of the nACh receptor
    -Mimics the effects of ACh but is not subject to breakdown by AChE.
    -Indication: neuromuscular blockade (short duration) for surgery
  • What is memantine?

    -Non-competitive NMDA receptor antagonist
    -Blocks overstimulation of NMDA receptors evident in Alzheimer's disease.
    -Indication: moderate to severe dementia of the Alzheimer's type.
  • What is Granisteron?

    -5-HT3 antagonist
    -5-HT mediates synaptic transmission to the medullary vomiting centre and area postrema.
    -Indication: Nausea and vomiting induced by cytotoxic chemotherapy or radiotherapy (oral or transdermal). Postoperative nausea and vomiting (intravenous).
  • What is diazepam?

    -Full agonist of the GABAA receptor
    -Potentiates GABA (inhibitory) activity, increasing Cl- influx.
    -Indication: short-term use in anxiety or insomnia, life-threatening acute drug-induced dystonic reactions, adjunct in acute alcohol withdrawal, status epilepticus, febrile convulsions, muscle spasm.
  • What is Ivermectin?

    -Irreversible agonist of the glycine receptor
    -Activates glycine receptor, hyperpolarisation of cells (influx of Cl-).
    -Indication: For the treatment of intestinal strongyloidiasis due to the nematode parasite Strongyloides stercoralis.
    -Also for the treatment of river blindness due to the nematode parasite Onchocerca volvulus.
  • What is Suramin?

    -Broad spectrum P2X receptor antagonist.
    -Blocks ATP activation of P2X receptors, leading to a change in intracellular Ca2+.
    -Used for parasite infections.
  • What are the major targets of drugs?
    -Enzymes
    -Transporters
    -Ion channels
    -Receptors
  • Define receptor:

    -Target molecules through which soluble physiological mediators can produce their desired biological effects
  • What are the 4 different types of receptors?
    -G-Protein coupled
    -Ligand-gated ion channels e.g., Nicotinic acetylcholine receptors
    -Enzymes coupled receptors
    -Nuclear receptors
  • What is a G-Protein coupled receptor?

    -Coupled to G proteins to indicate signal transduction
    -7 transmembrane domains
    -Largest family of cell-surface receptors with 800 genes
    -Represent 50% of current drug targets for stomach ulcers, allergies. hypertension. migraines and glaucoma.
  • What signals activate GPCRs?
    -Photons
    -Hormones
    -Peptides
    -Peptidases
  • Class A GPCRs

    -Rhodopsin like
    -short N-terminus
    -Agonists binds with extracellular loops & transmembrane domains
    -Majority of prescribed GPCR drugs are class A
  • Which GPCR receptors belong to class A?
    -B-adrenoceptors,
    -Histamine receptors
    -Dopamine receptors
  • Class B GPCRs

    -Secretin like
    -Larger, globular N-terminus; plays role in agonist binding
    -Currently no small molecule drugs on market
  • Which GPCR receptors belong to class B?
    -Secretin receptors
    -Calcitonin receptors
    -Glucagon receptors
  • Class C GPCRs

    ➟Metabotropic glutamate receptors
    ➟very large N-terminal domain binds agonists; form obligatory dimers
    ➟few small molecule drugs on market
  • Which GPCR receptors belong to class C?
    -Metabotropic glutamate receptors
    -GABA receptors
  • Second messengers example:

    -3'-5'-cyclic adenosine monophosphate (cyclic AMP)
  • Desensitisation of GPCRs

    -Molecular mechanism that prevents continuous activation of GPCRs; usually occurring within seconds
    -Achieved by phosphorylation and/or internalization
    -Critical to prevent uncontrolled signalling
  • What is homologous Desensitisation?
    -Effects are restricted to agonists acting through a specific receptor
  • What is heterologous Desensitisation?
    -Effects can affect receptors that share a component of the same signalling cascade
  • What is downregulation?

    -Reduction in the numbers of a functional receptor
  • What are the molecular events that occur after agonist binding which
    lead to internalisation of a GPCR?
    -Confirmational change
    -Phosphorylation
    -Binding of B-arrestins
    -Recruitment of clathrin
  • What is tolerance?

    -The progressive reduction in the effectiveness of a drug; usually occurring over days or hours
    -Cellular and molecular mechanisms are not necessarily specified and are often difficult to resolve
    -Does not involve change in receptor number
    -Problem in health care industry e.g., morphine