Medicines desgin Flashcards
Lec 6
3 main mechanisms of crossing the BBB
Passive transcellular diffusion- majority of drugs cross this way, favors lipophilic drugs
Active transport- Substances the brain needs can be transported this way against the concentration gradient eg glucose/amino acids
Receptor mediated transport- receptors used to transport substances that cannot cross otherwise eg insulin
Lec 6
Suggested parameter for CNS drugs
N+O<6 (with 0
No carboxylic acids
Lec 6
Definition of polar surface area (PSA)
PSA is the surface area of all the polar atoms + the attached hydrogen atoms
Lec 6
Definition of LogD
LogD is the LogP at a given pH
In the case of CNS this is measured at pH 7.4
Lec 6
Give two examples of drugs that utilise the pro-drug strategy to cross the BBB
Heroin-very lipophilic so cross BBB and is metabolized to morphine
Levodopa- transported across by amino acid transport carrier system and is metabolized to dopamine (DA)
Lec 6
How are internal H-bonds different to normal H-bonds?
Having internal H bonds as opposed to exposed H-bonds reduces their negative impact on CNS penetration
Lec 7
Pharmacological effects of opium comes from which compounds?
The alkaloids
Lec 7
Describe the metabolism of Heroin
Heroin (2x as potent, less affinity compared to morphine) metabolized to 6-acetylmorphine (4x as potent with a similar affinity to morphine)
6-acetylmorphine is further metabolized to morphine
Morphine can be broken down to two metabolites:
>Morphine-3-glucaronide (major metabolite, inactive,quickly excreted)
>Morphine-6-glucaronide (minor metabolite, more potent than morphine)
Lec 7
Why is codiene used for moderate pain relief?
Has 1/10 of the potency of morphine
However codeine remains active after oral administration while morphine suffers from significant 1st pass effect
Lec 7
Describe the effect of changing the N-methyl group on morphine
The analgesic effect initially decreases as the size of the substitute increases
However the analgesic effect increases again after this dip with activity peaking at C6 with the most active compound being N-beta-phenethylnomorphine
Lec 7
What is nalorphine?
Where the N-substituent is an allyl group
Antagonised effects of morphine by acting as an antagonist at the mu opioid receptor
Acts as a analgesic via agonism at the Kappa opioid receptor
Lec 7
Describe the general SAR of opiates
Changes of the N substituent changes efficacy
Changes at 6 position changes PK parameters
Changes at the 3 position changes potency and PK
Lec 20
What are benzomorphans?
They have had 1/2 of a ring removed and so have a simplified structure
They still retain much of their activity
Lec 20
What is the first fully synthetic opiate?
Pethidine
Discovered by accident during research into atropine
Lec 20
Describe the structure and activity of methadone
Binds only to mu receptors
No fused rings in structure
Similar binding and activity compared to morphine
Very lipophilic causing wide distribution and a milder but longer duration of action
