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Respiratory Diseases & Dermatology > MD1: SAR of B-Agonists & Antimuscarinics > Flashcards

MD1: SAR of B-Agonists & Antimuscarinics Flashcards

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Dermatology Board Prep flashcards
1
Q

what do salbutamol and ipratropium treat

A

symptoms of asthma and chronic obstructive pulmonary disease

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2
Q

what does COPD stand for

A

chronic obstructive pulmonary disease

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3
Q

what is the duration of onset of salbutamol

A

short-term relief due to short onset

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4
Q

what is the duration of onset for ipratropium

A

short-term relief due to short onset

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5
Q

what are two examples of short duration of action bronchodilators

A

salbutamol, ipratropium

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6
Q

what modifications can be made to convert lead compounds into selective agonists or antagonists

A

chain extension, conformational restriction, group shifting, chiral switching

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7
Q

where are lead compounds found

A 
natural receptor ligands like acetylcholine and noradrenaline
collections of synthetic compounds
existing drugs
natural products like muscarine
computer aided rational design
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8
Q

what are the features of the SAR on acetylcholine

A

the ester group (acetyl)
the nitrogen group (choline)
CH2-CH2 between ester and nitrogen group is needed

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9
Q

what structural features would not be tolerated when considering the SAR of acetylcholine

A

large esters

CMe3 instead of NMe3

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10
Q

what are the overall conclusions of SAR for acetylcholine

A

tight fit between ACh and receptor binding site (little scope for variation)
methyl groups fit into small hydrophobic pockets
ester inteacts by hydrogen bonding
quaternary nitrogen interacts by ionic bonding

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11
Q

how many variations of ACh are there

A

many

due to several freely rotatable single bonds

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12
Q

what are the two types of cholinergic receptor

A

nicotinic and muscarinic

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13
Q

what type of activity do cholinergic receptor types have

A

agonist

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14
Q

where are the receptors located that nicotine works on

A

cholinergic receptors at nerve synapses and skeletal muscle

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15
Q

where are the receptors located that L+-muscarine works on

A

cholinergic receptors on smooth and cardiac muscle

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16
Q

why are muscarine and nicotine rigid ACh analogues

A

the rotatable bonds of ACh are locked within a ring which restricts the number of possible conformations
this defines the separation of the ester and nitrogen in pharmacophores

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17
Q

what are the natural product leads in the development of cholinergic antagonists (muscarine)

A

atropine and hyoscine

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18
Q

what are the important binding groups in atropine and acetylcholine

A

amine and ester groups use ionic and H-bonding

the position of these groups is similar in both molecules

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19
Q

what group in atropine and acetylcholine needs to be protonated when bound to a receptor

A

nitrogen

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20
Q

how does atropine bind to receptors

A

the aromatic ring is an extra binding group (Van der Waals)
it binds with a different induced fit with no activation and is larger than ACh
it binds more strongly than ACh

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21
Q

what receptors do synthetic cholinergic antagonists work on

A

muscarinic receptors

22
Q

what are two examples of synthetic cholinergic antagonists

A

ipratropium and atropine methonitrate

23
Q

what does atropine methonitrate do

A

lowers GI motility

24
Q

what does ipratropium do

A

bronchodilator

25
Q

what happens to synthetic cholinergic antagonist analogues

A

they are fully ionised and unable to cross the blood brain barrier
they have no CNS side effects

26
Q

what are the important r]features of muscarinic receptor antagonists

A

they have an ionised tertiary amine or quaternary nitrogen; they have an aromatic ring; an ester group; their N-alkyl groups can be larger than methyl groups (unlike agonists); branching at aromatic/heteroaromatic rings is important

27
Q

what is the function of branching on aromatic/heteroaromatic rings of muscarinic receptor antagonists

A

they allow extra hydrophobic binding regions available next to normal ACh binding site

28
Q

what is the effect of activating a-adrenoreceptors

A

contraction of smooth muscle (except the gut)

29
Q

what is the effect of activating B2-adrenoreceptors

A

relaxing smooth muscle

30
Q

what is the effect of activating B1-adrenoreceptors

A

contracting cardiac muscle

31
Q

where do B2-adrenoreceptors predominate

A

the airways

32
Q

where do B1-adrenoreceptors dominate

A

the heart

33
Q

what type of molecule is noreadrenaline

A

neurotransmitter

34
Q

what type of molecule is adreneline

A

hormone

35
Q

what is the general structure of catecholamines

A

catechol group

alkylamine group

36
Q

what are the lead chemical messengers in the adrenic system

A

noreadrenaline, adrenaline

37
Q

what functional groups are on catecholamines

A

phenol (meta and para), alcohol, protonated amine

38
Q

how do phenol groups of catecholamines work

A

form H-bonds to binding site (especially B-adrenoreceptors)

meta-phenol can be replaced with other hydrogen bonding groups

39
Q

how do alcohol groups of catecholamines work

A

forms a hydrogen bond to the binding site (R-enantiomer more active)

40
Q

how do protonated amine groups of catecholamines work

A

forms an ionic interaction with the binding site

41
Q

how does the N-alkyl group of catecholamines work

A

affect target selectivity; larger N-alkyl groups lead to selectivity for B-adrenoreceptors

42
Q

how does the aromatic ring group of catecholamines work

A

forms Van der Waals interactions with the binding site

43
Q

what are the features of an adrenic binding site

A

hydrophobic pocket in B-receptors

44
Q

what are the features of isoprenaline

A

shows some selectivity for B-adrenoreceptors
bulky isopropyl group introduces B-selectivity by chain extension
but there is no selectivity between B-subtypes
there are cardiovascular side effects due to B1-receptors

45
Q

what are the features of isoetharine

A

shows selectivity for B2-adrenoreceptors
ethyl group introduces B2-selectivity
short lasting due to drug metabolism
metabolised by catechol-O-methyltransferase

46
Q

what are the features of salbutamol

A

hydroxymethylene group retains B2-agonist activity
moving the phenolic OH away from the ring by one atom prevents metabolism but still allows H-bonding with target receptor
same potency as isoprenaline
2000 times less active on the heart
duration of action 2-6hours
administered as a racemate by inhalation (R-enantiomer has been developed separately (levalbuterol in chiral switch))

47
Q

what does SAMA stand for

A

short acting muscarinic antagonist

48
Q

what is an example of a SAMA

A

ipratropium

49
Q

what does SABA stand for

A

short acting beta-2 agonist

50
Q

what is an example of a SABA

A

salbutamol

Respiratory Diseases & Dermatology (34 decks)

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