PH2113 - Neuropharmacology 5 Flashcards
What are the properties of metabotropic glutamate receptors?
Ca2+ sensing receptor - CaSR 2 GABA(B) receptors - 1 receptor, 2 subunits - taste receptors - sweet - umami 7 orphan receptors
What are the different groups of metabotropic glutamate receptors?
Group 1 - mGluR1 - mGluR5 Group 2 - mGluR2 - mGluR3 Group 3 - mGluR4 - mGluR6 - mGluR7 - mGluR8
Where are glutamate receptors found?
Group 1
- post synaptic
Group 2 and 3
- presynaptic
What is the function of glutamate receptors?
Modulate other receptors Modifiy excitotoxic activity - NMDA receptors Involved in synaptic plasticity Differential distribution in the brain
What are G-protein coupled receptors also known as?
Metabotropic receptors
7-TM receptors
How do 7-TM receptors work?
Equilibrium between active and inactive conformations
- dynamic proteins that interchange between different conformations that are stabilised by ligans
What effect do agonists have on 7-TM receptors?
Stimulate the receptor by stabilising an active conformation by various mechanisms
- binding between transmembrane segments
What effect do antagonists have on 7-TM receptors?
Stabilise one or more of the many different inactive conformations of the receptor and thus prevents the receptor from going into the active signalling conformation
What are the complexities of G-protein signalling?
Some GPCRs are constitutively active
- adrenoceptors
Inverse agonists
- decrease G-protein receptor binding and reduce basal activity of receptors or reduction in binding receptor affinity
- induces a conformational change in the receptor that can produce a variable affinity for different G-proteins thereby having different actions
What is an allosteric modulator?
Negative, positive and silent
Receptors can be regulated by sites distant to the agonist binding site
What is homodimerisation?
Classically assumed that GPCRs existed as monomers and interacted with G-proteins with a 1:1 stoichiometry
Evidence that many form dimers to express function
Dimerisation may be via covalent or non-covalent interactions and may involve extracellular domains and/or C-terminal tails
Complex interactions with multiple G-proteins
What is heteromeric dimersation?
In the case of GABA receptors, function requires heteromeric expression
Opioid d- and k- receptors also form functional heteromers
Increases functional diversity economically
What is direct signal amplification?
At each stage of signalling from the activation of the receptor to generating a cellular response, the initial signal (i.e. ligand binding) is amplified
Why is Drug Discovery and Development risky?
10% of new pharmaceutical agents entering clinical development reach the market
- CNS drugs entering clinical development lower probability
- 6%
- Industry average across other non-CNS therapeutic areas
- 15%
CNS drugs take longer in development and regulatory approval
- 12 - 13 years
compared with cardiovascular/gastrointestinal indications
- 6 - 8 years
Why do success rates in CNS drug development fall below average?
Complexity of the brain and ability to identify highly selective targets
Propensity for CNS drugs to cause CNS-mediated side effects
- nausea
- dizziness
- seizures
Presence of the Blood-Brain Barrier across which most therapeutic agents need to penetrate
- further pharmacokinetic hurdle
Lack of validated biomarkers readily amenable to early drug development to inform whether a given neurotherapeutic agent is reaching the brain in sufficient concentrations to modulate the desired CNS target
