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DONE Drug Design and Discovery > Stephen Husbands - The Opioids > Flashcards

Stephen Husbands - The Opioids Flashcards

1
Q

Pharmacological effects of Morphine are produced by the…

A

Alkaloids

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2
Q

Morphine is ____ due to it’s tertiary amino group

A

BASIC

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3
Q

The N-methyl group of Morphine can convert between the ___ and ___ positions

A

Axial and Equatorial

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4
Q

In order to see what functional groups were important for analgesia, chemists can create different ______

A

Analogues

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5
Q

Modifying or removing the 6 hydroxy group of Morphine does what to analgesic properties?

A

Doesn’t affect analgesia

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6
Q

Activity of Morphine is dependant on what 3 points?

A
  • Phenol ring
  • Aromatic ring
  • Tertiary amine
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7
Q

What happens to the tertiary amine of morphine when it interacts with it’s target site?

A
  • It is protonated and ionised - forms ionic bonds
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8
Q

What interaction does the phenol of Morphine have with the target site?

A
  • Hydrogen bonding
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9
Q

What interaction does the aromatic group of Morphine have with the target site?

A
  • VDW forces
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10
Q

What bonding does the tertiary amine of Morphine have with the target site?

A
  • Ionic bonding - through protonated and ionised nitrogen
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11
Q

What are the 3 main types of opioid receptor?

A

Kappa, Mu and Delta

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12
Q

Activation of which receptor results in the strongest analgesic effects?

A

Mu

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13
Q

Which receptor results in the strongest and most dangerous side effects? They are…

A

Mu

  • Resp depress
  • Addiction
  • Euphoria
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14
Q

What does pharmacodynamics refer to?

A
  • Ability of drug to bind to it’s target and produce pharmacological effect
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15
Q

The phenol acts as a hydrogen bond…

A

Donor - forms bond with hydrogen bond acceptor in target site

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16
Q

The aromatic ring of morphine can form _____ forces with hydro____ sites in the binding site

A

VDW forces with hydrophobic sites in the binding site

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17
Q

Pharmacokinetics refers to…

A

Ability of drug molecule to reach target and survive in the body

18
Q

Morphine is relatively… polar or non polar?

A

POLAR

19
Q

The amine group of morphine is a ____ base so morphine can exist in the free base and ionised form. What does this mean in relation to crossing the BBB?

A
  • It is a WEAK base

- This means unionised form of Morphine can cross the BBB whereas the ionised form of Morphine cannot

20
Q

Once the free base of Morphine has crossed the BBB it must ____ in order to interact with the target binding site

A

IONISE

21
Q

If the 6 Hydroxy group of Morphine is altered then the pharmaco____ of the molecule will change…

A

PharmacoKINETICS

22
Q

Give an example of how changing the 6 hydroxy group of morphine will change it’s pharmaco______

A

If the 6 hydroxy group of Morphine is made more NON polar e.g making it an acetyl group (6-acetylmorphine) then it is more able to cross the BBB and be absorbed due to it’s high lipophilicity, increasing it’s potency

23
Q

Heroin differs from Morphine in what way?

A
  • The phenol has been acetylated
  • The 6-hydroxy group have been acetylated
  • It is more potent than morphine
  • The 3-acetyl group requires hydrolysis before it can interact with the receptor via H bonding (phenol group)
24
Q

Codeine undergoes what type of metabolism to form what?

A

O-demethylation to form Morphine

25
Q

Medicinal chemists tried altering the N-methyl group of Morphine and found what?

A
  • Increasing the size of the change by adding a butyl group decreased activity
  • Increasing the size of the change past butyl increased activity slightly again
  • Adding a lipophilic phenethyl ring dramatically increased activity!
26
Q

What did the addition of a lipophilic ring to the N-methyl group of Morphine suggest?

A
  • That a hydrophobic binding region is present in the binding site
27
Q

Nalorphine has an allyl group off the Nitrogen - what does this mean?

A
  • It is an antagonist at the Mu receptor

- It is a weak agonist at the Kappa receptor

28
Q

Removing the ring with the 6-hydroxy group results in the formation of…

A

Benzomorphans

29
Q

Benzomorphans ____ analgesic activity

A

retain

30
Q

List some different clinical difference between morphine and methadone

A

Methadone:

  • Less severe side effects
  • Less emetic effects
  • Less sedation
  • Less euphoria
31
Q

Methadone is a __phenyl____amine

A

Diphenylpropylamine

32
Q

Explain the test that was conducted with Naloxone to test for stereospecific binding…

A
  • Naloxone radiolabelled
  • Measured binding under 2 conditions

1) XS non radiolabelled naloxone
2) XS non radiolabelled naloxone enantiomer

Less binding in condition 1
More binding in condition 2 - as enantiomer doesn’t specifically bind receptor - diff stereochemistry

STEREOSPECIFIC BINDING PROVED

33
Q

Morphine and enkephalins have WHAT in common?

A

Tyrosine skeleton (phenol attached to the ring through to the tertiary amine) - both interact with the same aspartic acid residue in the receptor site

34
Q

The MESSAGE part of a molecule is responsible for what?

A

Pharmacological activity

35
Q

The ADDRESS part of a molecule is responsible for what?

A

Target selectivity

36
Q

Kappa specificity is due to WHAT?

A
  • A basic nitrogen on the address part of the molecule
37
Q

The presence of WHAT can make a nitrogen unable to protonate and therefore reduce kappa specificity and potency of the compound?

A

An oxygen - amide group.

As electrons interact with the carbonyl

38
Q

Antagonism is due to presence of what?

A
  • Cyclopropyl group off nitrogen on message
  • Cyclobutyl group off nitrogen on message
  • Allyl group off nitrogen on message (double bond)
39
Q

Delta specificity is due to what?

A
  • Aromatic ring presence on address
40
Q

Mu specificity is due to what?

A
  • Presence of double bond oxygen group off aromatic ring
41
Q

What are the 4 strategies in developing Morphine analogues?

A
  • variation of substituents (aromatic, nitrogen, 3-OH)
  • drug extension (adding chains to nitrogen to see if further binding sites present between analogue and receptor e.g hydrophobic region?)
  • simplification - remove rings of skeleton to see if needed or not for pharmacological effect
  • rigidification - add extra ring to increase rigidity - diels-alder adduct - Addition of ketone group and undertaking Grignard reaction adds acetylates 6-OH group and the ketone inc lipophilicity and inc potency
42
Q

All analogues with the phenylpiperidine ring in the equatorial configuration are… ASK ???

A

antagonists - independent of the R group

DONE Drug Design and Discovery (9 decks)

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