Medicines Design - Husbands Flashcards
What is the effect of stress on CREB?
CREB causes the release of dynrophin (a kappa agonist), which stimulates GABA production, which inhibits dopaminergic neurones
This can cause a lack of pleasure at doing certain things (anhedonia)
Why is it often vital to test compounds in the correct animal model?
BU08028 in mice showed a full agonist response at mu and zero effects at NOP
In humans it showed the action at NOP and the partial agonism at mu that was expected
This was the same drug!!!
What produces the pharmacological effects in opium?
The alkaloids
What affect could acetylisation have on a drug?
Increase lipophilicity, and so BBB penetration
Could also reduce side effects
What is the relationship between NOP and buprenorphine?
Buprenophine (a mu partial agonist) is also an agonist at NOP receptors which has a synergistic effect with mu, just without the side effects!
So a full analgesic effect can be recieved by just a partial agonist
What is Laudanum?
An opioid in ethanol (alcohol)
What are the 5 main things that will effect a drugs ability to get into the brain?
The number of H-bonding groups (donor and acceptor) –> Maximum of 1
Lipophillicity –> LogD (taken at pH of interest) = 1-3
Polar Surface Area (PSA) –> Total surface of polar atoms (eg, oxygen and nitrogen) = <90A with less than 6 N+O
Molecular Weight –> <400Da
Acidity –> No acids are best
Which diastereoisomer of tertiary alcohols can give a greater analgesic potency when specific alkyl groups are added
The one with the R group in the middle
What are the 3 basic ways of getting drugs into the brain?
Passive Diffusion –> Used mainly by lipophillic molecules
Active Transport –> Molecules that are needed like glucose and AAs are moved via transport proteins
Receptor-Mediated Transport (endocytosis) –> For drugs like insulin
What are the 3 functional moieties that are needed for an NOP agonist
A) A heterocyclic moiety
B) A group containing a basic nitrogen
C) A lipophillic moiety attatched to the basic nitrogen
What is common to all ‘morphine like’ drugs?
An axial aromatic ring
What is Buproprion?
And why is its effects often only modest?
A dopamine and NA reuptake inhibitor with antidepressent effects
Often used in smoking sessation
It acts to simulate POMC neurones, which have anorexigenic effects –> Helping people lose weight
However this stimulation can lead to compensatory autoinhibitory feedback by endogenous opioids…causing limited weight loss
What are the best groups to add to the following drug?
Why is there a high interest in CB1 antagonists as anti-obesity drugs?
And what is Rimonabant’s main problem?
It is well known that cannabis will stimulate feeding, so logic states that by antagonising CB1 we will prevent feeding
The main problem is it is too lipophillic –> Analogues have been made to reduce this
What are 2 key components of a drug that can access the brain?
An aromatic ring
A basic nitrogen
Explain the effects of Nalorphine
Antagonist at Mu –> reversing the effect of morphine
Agonist at Kappa
Decrease: MW and PSA –> Could remove large aromatic groups
Increase: The ClogP (lipophilicity) –> could be done by removing H-bonding groups
In terms of CNS drugs, what is the significance of internal H-bonds?
They reduce the negative impact on CNS penetration
What do we affect by changing specific groups?
What is the main active metabolite of heroin?
And how is it made?
6-monoacetylmorphine
Via hydrolysis with water
What’s a benzomorphan?
A simplified opioid, made by removing several aromatic groups
It’s activity is pretty much the same as morphine despite the changes
What is an Enkephalin?
And what is their main problem?
Endogenous opioids
Tyrosine (in all enkephalins) is highly flexible (amine group), meaning that D-Tyr will bind whilst L-Tyr may not
When replacing the nitrogen methyl group in opioids, at what carbon length is the maximum anaglesic effect achieved?
6 carbons
What is Alvimopan?
A preventative agent of opioid caused GI problems
The nitrogen is protonated at physiological pH, so wont cross the BBB….meaning it only works in the periphery, which is perfect!!
What is Buprenorphine?
A partial mu opioid agonist and full kappa antagonist
What is the base molecule that etorphine is based on?
Codeine or Morphine?
Morphine (3-OH not MeO)
What is the most active form of methadone?
L-(R)-Methadone
Sold as a racemic mixture (D-isomer has NMDA antagonist activity)
Why does methadone only need to be taken once daily?
More lipophillic than drugs like morphine, so it is more widly distributed, meaning it has a greater duration of action
What does increasing LogD do?
Increases the lipophillicity, which means a greater BBB penetration (up to a point)
Why could mu opioid receptor antagonists/inverse agonists be useful in treating obesity?
As mu receptors are used in the reward pathway when eating, so by having inverse agonists or antagonists at mu we could reverse the effect
What is the address molecule for delta and kappa opioid antagonists?
Delta –> 2nd aromatic ring
Kappa –> Spacer then 2nd basic nitrogen (or other small cation)
