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| Question | Answer |
| Which form of glutamate binds more strongly to NMDARs and is more active? | S-glutamate |
| Which group on glutamate can cause it to become ionised and how? | Amine group - picks up a proton when in solution |
| Which bonds allow for rotation? | Single bonds |
| What are the two stable forms which S- glutamate is likely to resemble and what percentage of each form in solution? | Folded (18%) Extended (6%) |
| What is the first stage of drug discovery? | Alter lead compounds to determine which are key to activity of drug |
| What are the main components of glutamate? | Amine group - NH a-carboxylic acid group linker chain (CH2-CH2) Terminal acid group |
| What happens if you remove any of the component groups of glutamate? | It loses all activity at NMDAR |
| What is added to glutamate to form NMDA (methyl-1-D-Aspartate) | A methyl group to the amine group |
| What can you use to block the rotation of bonds? | Cyclopropyl |
| What is L-CCH-I? | An agonist at group 1,2 and 3 mGluR |
| What is LCCG-IV | An agonist at NMDAR |
| Which form of glutamate acts at mGluR? | Extended form |
| Which form of glutamate acts at NMDAR? | Folded |
| What does the a-carboxylic acid group of glutamate bind to at the GluN2A receptor? Via which bonds? | Binds to the arginine residue. Hydrogen and ionic bonds. |
| What does the terminal carboxylic acid group of glutamate bind to at the GluN2A receptor? Via which type of bond? | Binds to threonine and serine residues via hydrogen bonds. |
| What does the a-amino group of glutamate bind to at the GluN2A? Via what kind of bonds? | 1) To Serine and Threonine via hydrogen bonds. 2) To the carboxylate group on an aspartate residue via a water molecule. |
| What changes are made to to turn S-Glutamate into an NMDAR antagonist. What is this first antagonist formed called? | Linker length is increased to 3 or 5 CH2 groups. Stereochemistry is changed to R. R-a-aminoadipic acid |
| What is kD of R-a-aminoadipic acid? | 40uM |
| What are the two NMDAR antagonists that can be made from R-a-aminoadipic acid? How are they made and how do they differ? | Phosphonate group displaces terminal acidic group R-AP5 > 3CH2 R-AP7 > 5CH2 |
| What are the Kd of R-AP5 and R-AP7? Which is therefore more potent? | R-AP5 ~ 0.7um R-AP7 ~ 1.5um R-AP5 is more potent |
| How can you block NMDAR and KAR currents? What effect did adding 50uM R-AP5? | Use TTX to block Na channel currents/depolarisation. Adding NMDA/Kainate causes depolarisation of the postsynaptic neuron. R-AP5 blocks current through the NMDAR receptor but not the kainate. |
| Why does the phosphonate group on AP5 mean that is is a more potent antagonist than R-a-aminoadipic acid? | Phosphonate group is tetrahedral and can at physiological pH form a an mono-anion or di-anion. Because of this compared to the planar R-a-aminodipic acid which can only form a mono-anion it binds with more affinity. PHOSPHONATE GROUP HAS MORE OPPORTUNITY TO INTERACT WITH RECEPTOR. |
| What do you do to turn AP5 to CGP40116? | Add a double bond between the 2nd and 3rd CH2 groups in the linker chain. |
| How do you transform AP7 into CPP? What then forms? | Replaces the second CH2 group with a nitrogen atom, causing a ring containing the two nitrogen molecules to form. |
| How do you transform CPP to CPPENE? | Add a double bond to the last CH2 group (closest to the phosphonate group). |
| What are the four things that can be done to increase antagonist efficacy? | 1) Linker has 3 or 5 Ch2 groups 2) Phosphonate group should replace carboxylic acid terminal 3) Reduce movement of bonds (double bond or ring bond incorporate) 4) Have R stereochemistry |
| Define bioavailability | Ability of drug to reach it's site of action in the body |
| When is bioavailability studied? | During the pharmacokinetics phase of the trial. |
| What three factors can bioavailability depend on? | 1) Ability to cross membranes (eg BBB or Gastrointestinal mucosa) 2) First pass metabolism in the liver (is it broken down into something else) 3) Absorption and excretion properties of the drug |
| In what state does a drug need to be in order to cross a membrane? What type of drug is better at crossing membranes? | Unionsed. Lipophilic. |
| What can you turn a drug into to get it across the blood brain barrier - how do you this? How do you turn it back into the ionised form? | Convert the acid into an ester - once it is across the BBB it can be converted back into an acid by an esterase. |
| What happens to amino, carboxylic and phosphonate groups at a physiological pH? | They are all ionised. |
| What part of the antagonist does esterification effect? | The remaining carboxylic acid group - add a CH2CH3 group |
| Other than making a pro drug what adaptation can you perform on a drug to help it cross barriers? | Add a lipophilic group such as a biphenyl ring. |
| What are the benefits of adding a biphenyl ring? (2) | Provides substrate for transporter - actively transporter from gut to blood Orally available. |
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