neuropharmacology Flashcards
what is a drug
a chemical substance of known structure, other than a nutrient or essential dietary ingredient which, when administered to a living organism, produces a biological effect.
what targets do drugs act on
receptors
enzymes
carriers
ion channel
what is a receptor
protein molecules whose function is to recognise and respond to endogenous chemical signs.
when is a receptor activation
when a ligand binds
higher affinity for activated state
conformational change
agonist
drugs which activate receptors
towards activated state
antagonist
a drug that binds to the receptor without causing activation
blocks activation reduces ability of ligand binding
e max
maximal drug response
EC50
concentration of drug that gives half maximal response
concentration respose graph shape
non linear relationship
sigmoidal curve
neural antagonist
an antagonist that doesn’t have positive or negative efficacy
blocking binds to receptor without producing an effect
efficacy = 0
inverse agonist
binds to receptor produce opposite response
as the conc increases, it decreases the amount of receptors in the activated state
directly causes a change from the active to resting state.
reversible antagonist
compete with agonist binding typically at the same site
binds reversibly
irreversible / covalent antagonist
binds irreversible to receptor
may change the conformation of the receptor to reduce ability of agonist to bind
lower curve
full agonist
sigmoidal curve
all receptors in activated state
increases as ligand binds
partial agonist
60% of receptors in activated state
lower efficacy
smaller response curve
affinity
how well a drug binds its receptor
efficacy
how well a drug once bound to a receptor elicits a response
potency
a measure of the amount of drug required to elicit a response of a given intensity
how does a irreversible antagonist work
the covalent bond produces a conformational change that the receptor is unable to become acivated again.
potency on the graph
location of curve along dose axis
more to the left = more potent
efficacy on graph
location of the curve on the resoponse axis
higher the curve = higher efficacy
orthosteric site
the primary ligand binding site of a receptor
allosteric site
a site distinct from the endogenous ligand
positive allosteric modulator effect on signalling
increase signalling
site separate to orthosteric site
increase affinity and efficacy
causes curve to shift to the left and up
negative allosteric effect on signalling
decrease signalling
decrease affinity and efficacy
causes curve to shift to right and down
neurotransmitter
biochemical that mediated fat action direct communication between 2 neurons (pre and post synaptic)
neuromodualtor
biochemical that modulates activity of neurons and neural networks by changing the ability of neurons to repose to neurotransmitters
can act at sites remote from where they are synthesised
glutamate
excitatory
aspartate
excitatory
GABA
inhibitory
glycine
excitatory or inhibitory
Biogenic amines
ACh
Mono-amines
Histamine
Catecholamines
Serotonin (5HT)
Noradrenaline
Adrenaline
Dopamine
give examples and targets of small molecule transmitters
glutmate, serotonin, GABA, dopamine, ACh
Ligand gated ion channels, GPCRs
give examples and targets of neuropeptides
substance P, neuropeptide Y , endorphins
GPCRs
give examples and targets of lipid mediators
prostoglandins
endocannabioids
GPCRs
give examples and targets of nitric oxide
Guanylyl cyclase
give examples and targets of neutorophins, cytokines
brain derived neurotropic factor, IL-1
kinase linked receptors
neuronal growth plasticity
give examples and targets of steroids
androgens, oestrogens
nuclear and membrane receptors
plasticity
how does nitric oxide signalling modulate neurotransmission
-Ca2+ influx into cells downstream of ion channels opening leads to activation of nNOS
- increases intracellular NO levels
-NO activates cGMP and MAPK signalling –> modulated function of the postsynaptic neurone
- NO can diffuse retrogradely and impact NT release from the presynaptic neurones.
what do glial cells do with neurotransmitter
release transmitters which can modulate neuronal activity
what do glial cells do with neurotransmitter
release transmitters which can modulate neuronal activity
examples of gliotransmitters
glutamte
ATP
adenosine
D serine
Eicosanoids (prostaglandins)
cytokine(TNFalpha)
neuopeptides
inotropic receptors
ligand gated ion channels
NMDA, AMPA, Kinate
fast
metabotropic receptors
receptors that coupe through secondary messenger
GPCRs and tyrosine kinase linked receptors
may indirectly regulate ion channel openings
features of ligand gated ion channels
Heteromeric assemblies of 4/5 subunits
each subunit has transmembrane spanning helices which when assembled form a central aqueous channel
ligand binding - channel opening = millisecond - fast
mechanism of GPCR
ligand binding induced GDP to GTP exchange on G alpha subunit
G alpha subunit dissociates from beta-gamma complex
G alpha and beta-gamma complex activate downstream targets
when bound to target GTPase activity of G alpha subunit is increased leading to hydrolysis of GTP to GDP
name some downstream effectors of stimulation of GPCRs
Adenyl cyclase - cAMP formation
Phospholipases
PLC = inositol phosphate and diacylglycerol formation
PLA2 = arachidonic acid and ecodanoid formation
kinase = MAPK, PI3K
ion channels
gene transcription = via MAPK, PKA/CREB
G alpha s
- stimulates adenylyl cyclase = causing increased cAMP formation
G alpha i/o
inhibits adenylyl cyclase = causing decreased cAMP formation
G alpha q
activated phospholipase C = increasing production of second messengers = Inositol triphosphate and diacylglycerol
what metabotropic glutamate receptors single through Gq
group 1 = mGlu1, mGLu5
slow excitatory
what metabotropic glutamate receptors single through Gi/o
group 2 mGul2,mGlu3
and
group3 3 mGlu4, mGlu6-8
slow inhibitory
how do kinase linked receptors work
ligand binding leads to dimerisation of receptors
receptor dimers undergo autophosphorylation at tyrosin residues
pTyr sites recruit proteins with Sh2 domains leading to activation of downstream signalling
what downstream signalling can be activated by kinase linked receptors
STAT, RAS/Raf/MAPK
what type of receptor are cytokine receptors
tyrosine linked receptors
cytokines = neuromodulators in CNS
activate multiple down stream signalling cascades = transcription factors
how is cytokine signalling regulated
regulated by endogenous negative feedback mechanisms
examples of nuclear (hormone) receptors
glucocorticoid receptor
oestrogen receptor
androgen receptors
how do nuclear (hormone) receptors work
steroid hormone passes through plasma membrane
inside target cell - steroid hormones binds to a specific receptor protein in cytoplasm or nucleus
receptor/ steroid hormone complex enters the nucleus and binds to DNA
gene transcription
protein synthesis induced
protein is produced
when does receptor desensitisation occur
high levels and chronic agonist exposure
what is receptor desensitisation
reduced signalling response to agonist binding
- uncoupling of agonist binding from signalling
- receptor internalisation
- reduced receptor expression (increased degradation and reduced synthesis)
tachyphylaxis
medical term for actor sudden decrease in response to drug after administration
tolerance
reduced response to drug after chronic use
addiction
behavioural manifestation of tolerance
what is homologous desensitisation of GPCRs mediated by
Arrestins
how are GPCRs desensitised
agonist binds to receptors
activated receptor
receptor phosphorylated by GPCr specific kinase
Beta arrestin is recruited
loss of G protein coupling
endocytosis and internalisation
how does densensitiation lead to drug tolerance
rapid desensitisation
- phosphorylation
- arrestin bindng
- endocytosis
short term tolerance
long term tolerance
