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CH 456 Medicinal Chemistry > Chapter 24 > Flashcards

Chapter 24 Flashcards

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1
Q

______ are a narcotic analgesics structurally related to morphine

A

opiates

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2
Q

______ are all naturally occurring, semi-synthetic, synthetic and endogenous compounds that interact with opioid receptors

A

opioids

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3
Q

______ contains a complex mixture of over 20 alkaloids

and the principle alkaloid in the mixture is morphine

A

Opium

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4
Q

____ was first isolated in pure form in 1803 and not until 1833 that chemists at the Edinburgh firm of Macfarlane and Co. (now Macfarlane-Smith) were able to isolate and purify it on a commercial scale

A

Morphine

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5
Q

True or False: because morphine is poorly absorbed orally, it was little used in medicine until the hypodermic syringe was invented in 1853

A

Tfue

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6
Q

In ______, Sir Robert Robinson proposed the correct structure in 1925, a full synthesis was achieved in 1952, and the structure was finally proved by X-ray crystallography in 1968

A

Morphine

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7
Q

analgesic activity is retained in the structures, indicating that neither of these groups is crucial to activity in this group

A

6-ethylmorphine, 6-acetylmorphine, 6-oxomorphine, hydromorphone and dihydromorphine

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8
Q

analgesic activity drops significantly in these structures, indicating the importance of the phenolic group

A

codeine, 3-ethylmorphine, 3-acetylmorphine and dihydrocodeine

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9
Q

What are the 3 important functional groups for analgesic activity?

A

phenol OH group
aromatic ring
tertiary amine
-protonated and ionized when the drug interacts with its target binding site

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10
Q

The structure of morphine consists of five rings forming a _______

A

T‐shaped molecule.

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11
Q

Morphine is a powerful analgesic but has various side effects, the most serious being _____, ______, and _______.

A

respiratory depression, tolerance and dependence.

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12
Q

What are the three main types of analgesic or opioid receptor that are activated by morphine?

A

mu (μ) receptors (aka MOR)
kappa (κ) receptors (aka KOR)
delta (δ) receptors (aka DOR)

all are G-protein-coupled receptors

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13
Q

True or False: Morphine acts as an agonist at all three types of receptor and activation leads to a variety of cellular effects depending on the type of receptor involved

A

True

these include the opening of potassium ion channels, the closing of calcium ion channels or the inhibition of neurotransmitter release

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14
Q

True or False: Agonist binding to MORs can result in the activation of multiple downstream pathway

A

True

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15
Q

the ______ is protonated and charged, allowing it to form an ionic bond with a negatively charged region of the binding site

the ______ acts as a hydrogen bond donor and forms a hydrogen bond to a hydrogen bond acceptor in the binding site

the rigid structure of morphine means that its _______ has a defined orientation with respect to the rest of the molecule, allowing van der Waals interactions with a suitable hydrophobic location in the binding site

A

amine nitrogen

phenol

aromatic ring

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16
Q

True or False: morphine is relatively polar and is poorly absorbed from the gut, and so it is normally given by intravenous injection and only a small percentage of the dose administered actually reaches the analgesic receptors in the central nervous system (CNS) due to the blood–brain barrier

A

True

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17
Q

True or False: however, the amine group is a weak base and so morphine can exist both as the free base and ionized form so morphine can cross the blood–brain barrier as the free base then ionize in order to interact with the opioid receptors

A

True

the pKa values of useful analgesics should be 7.8–8.9 so there is an approximately equal chance of the amine being ionized or unionized at physiological pH

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18
Q

Codeine is a prodrug that is converted in the body to morphine by _______

A

O-demethylation

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19
Q

Morphine binds most strongly to the ______ receptor. This receptor is responsible for the serious side effects associated with morphine.

A

μ

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20
Q

The ____ receptor is responsible for analgesia and sedation, and lacks serious side effects. However, activation causes psychological side effects which have prevented κ-selective opioids reaching the market.

A

k

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21
Q

The _____ receptor is favoured by the enkephalins.

A

δ

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22
Q

Some analgesics such as _____ and ______ act as prodrugs for morphine.

A

codeine and diamorphine

23
Q

introduction of a______ at position 14 increases activity for structures such as oxymorphone and oxycodone, and suggests that there might be an extra hydrogen bond interaction taking place with the binding site

A

hydroxyl group

24
Q

when a ______ is attached to the nitrogen atom, the activity increases 14-fold relative to morphine—a strong indication that a hydrophobic binding region has been located which interacts favourably with the new aromatic ring

A

phenethyl group

25
Q

______ is the addition of extra functional groups to a lead compound in order to probe for extra binding regions in a binding site

A

Drug extension

26
Q

What are 4 againsts of morphine?

A

Naloxone, naltrrexone and nalmefrene (cyclopropylmethyl), and nalorphine

27
Q

removing the oxygen bridge, as well as the alcohol and alkene functional groups gives a series of tetracyclic compounds called the ______ and these have useful analgesic activity and demonstrate that the oxygen bridge is not essential

A

morphinans

28
Q

_____ is class of opioids known as the 4-anilinopiperidines and is among the most potent agonists known for the ______receptor and also lack a phenolic group and are very lipophilic

A

fentanyl, μ

29
Q

True or False: fentanyl itself is up to 10 times more active than morphine as a sedative and analgesic

A

False, 100

30
Q

______ was designed to have a very short duration of action by introducing ester groups which are rapidly metabolized by non-specific esterase enzymes (surgery)

A

remifentanil

31
Q

_____ was discovered in Germany during the Second World War and is comparable in activity to morphine and is orally active and has less severe emetic and constipation effects and the side effects such as sedation, euphoria and withdrawal symptoms are also less severe

A

Methadone

given to drug addicts as a substitute for morphine or heroin in order to wean them off these drugs

32
Q

_______ of morphine are easily synthesized by demethylating morphine to normorphine, then alkylating with alkyl halides.

A

N-Alkylated analogues

33
Q

True or False: The addition of suitable N-substituents results in compounds which act as antagonists or partial agonists. Such compounds can be used as antidotes to morphine overdose, as treatment for addiction, or as safer analgesics.

A

True

34
Q

________ is a synthetic agent which contains part of the analgesic pharmacophore present in morphine. It is administered to drug addicts to wean them off heroin.

A

Methadone

35
Q

N-Phenethylmorphine and N-Allylmorphine binding interactions with the active and inactive conformations of the opioid receptor is in the _____ region

A

hydrophobic

36
Q

What is the difference between, met- and leu- enkephalin?

A

H-Try-Gly-Gly Phe- Met-OH

H-Try-Gly-Gly Phe- Leu-OH

37
Q

What is the difference in comparison of morphine and Met-enkephalin?

A

Additional interaction with receptor

38
Q

What are the three proposed binding interactions of an enkephalin with its receptor binding site

A

Pbinding (phenol)

Ionic binding (NH3)

Tbinding (tyrosine)

39
Q

What is the difference between the interaction of morphine with proposed binding site and the one for enkephalin

A

no p binding site for morphine

40
Q

What is an alternative approach to pain relief (peptidase inhibitor)

A

enhance the activity of natural enkephalins by inhibiting the peptidase enzymes which metabolize them (enkephalinases)

the enzyme responsible for metabolism has a zinc ion present in the active site, as well as a hydrophobic pocket which normally accepts the phenylalanine side chain present in enkephalins

a dipeptide (l-Phe-Gly) was chosen as the lead compound and a thiol group was incorporated to act as a zinc ion binding group

41
Q

What was the result of the peptidase inhibitor?

A

result was a structure called thiorphan, which was shown to have analgesic activity

42
Q

_____ is used in some countries for the treatment of diarrhoea actually a prodrug for thiorphan, which is formed after hydrolysis of the ester and thioester groups

A

racecadotril Z(peptidase inhibitor)

43
Q

it is believed that the tolerance and dependence effects associated with μ-agonists might be caused by their interaction with_______ rather than by interaction with unassociated μ receptors

A

δ-μ heterodimers,

44
Q

a bivalent ligand (MDAN-21) consisting of the μ-selective agonist_______ linked to the δ-selective antagonist _______ has been found to have 50-fold more potency than morphine, without causing tolerance or dependence

A

oxymorphone, naltrindole

45
Q

_______ has exciting potential for the development of a new generation of safer opioid analgesics with fewer side effects

A

Heterodimeric receptors are of current interest

46
Q

________ found that psychotomimetic (capable of producing an effect on the mind similar to a psychotic state) and dysphoric (profound state of unease or dissatisfaction) side effects were associated with activation of the______.

A

Highly selective κ-agonist,

κ receptor

47
Q

_______ are another approach has been to design opioids that act on the peripheral nervous system rather than the CNS such as ______ that is a PEGylated opioid antagonist prepared from naloxone

A

Peripheral-acting opioids
naloxegol

approved in 2014 for the treatment of opioid-induced constipation

PEGylation prevents the drug crossing the blood–brain barrier into the CNS

48
Q

true or False: It is proposed that there are two accessory hydrophobic binding regions in the receptor binding site. An agent will act as an agonist or antagonist depending on which of these regions it can access

A

True,

49
Q

Enkephalins, dynorphins, endomorphins, and endorphins are peptides which act as the body’s natural painkillers. The presence of an ______ is crucial to activity.

A

N-terminal tyrosine

50
Q

Analogues of enkephalins have been designed to be more stable to peptidases by the inclusion of _______, _______ or ________

A

unnatural amino acids, d-amino acids or N-methylated peptide links.

51
Q

_______ may have a future role as analgesics by inhibiting the metabolism of enkephalins

A

Enkephalinase inhibitors

52
Q

The _______ has been used to design opioids that are selective for a particular type of opioid receptor.

A

message-address concept

53
Q

The existence of ______ and _______ opioid receptors has an important role in understanding the activity of opioids and in designing novel opioids.

A

homodimeric and heterodimeric

CH 456 Medicinal Chemistry (7 decks)

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