MD1: SAR of B-Agonists & Antimuscarinics

Question 1

what do salbutamol and ipratropium treat

Answer 1

symptoms of asthma and chronic obstructive pulmonary disease

Question 2

what does COPD stand for

Answer 2

chronic obstructive pulmonary disease

Question 3

what is the duration of onset of salbutamol

Answer 3

short-term relief due to short onset

Question 4

what is the duration of onset for ipratropium

Answer 4

short-term relief due to short onset

Question 5

what are two examples of short duration of action bronchodilators

Answer 5

salbutamol, ipratropium

Question 6

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

Answer 6

chain extension, conformational restriction, group shifting, chiral switching

Question 7

where are lead compounds found

Answer 7

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

Question 8

what are the features of the SAR on acetylcholine

Answer 8

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

Question 9

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

Answer 9

large esters

CMe3 instead of NMe3

Question 10

what are the overall conclusions of SAR for acetylcholine

Answer 10

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

Question 11

how many variations of ACh are there

Answer 11

many

due to several freely rotatable single bonds

Question 12

what are the two types of cholinergic receptor

Answer 12

nicotinic and muscarinic

Question 13

what type of activity do cholinergic receptor types have

Answer 13

agonist

Question 14

where are the receptors located that nicotine works on

Answer 14

cholinergic receptors at nerve synapses and skeletal muscle

Question 15

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

Answer 15

cholinergic receptors on smooth and cardiac muscle

Question 16

why are muscarine and nicotine rigid ACh analogues

Answer 16

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

Question 17

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

Answer 17

atropine and hyoscine

Question 18

what are the important binding groups in atropine and acetylcholine

Answer 18

amine and ester groups use ionic and H-bonding

the position of these groups is similar in both molecules

Question 19

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

Answer 19

nitrogen

Question 20

how does atropine bind to receptors

Answer 20

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

Question 21

what receptors do synthetic cholinergic antagonists work on

Answer 21

muscarinic receptors

Question 22

what are two examples of synthetic cholinergic antagonists

Answer 22

ipratropium and atropine methonitrate

Question 23

what does atropine methonitrate do

Answer 23

lowers GI motility

Question 24

what does ipratropium do

Answer 24

bronchodilator

Question 25

what happens to synthetic cholinergic antagonist analogues

Answer 25

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

Question 26

what are the important r]features of muscarinic receptor antagonists

Answer 26

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

Question 27

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

Answer 27

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

Question 28

what is the effect of activating a-adrenoreceptors

Answer 28

contraction of smooth muscle (except the gut)

Question 29

what is the effect of activating B2-adrenoreceptors

Answer 29

relaxing smooth muscle

Question 30

what is the effect of activating B1-adrenoreceptors

Answer 30

contracting cardiac muscle

Question 31

where do B2-adrenoreceptors predominate

Answer 31

the airways

Question 32

where do B1-adrenoreceptors dominate

Answer 32

the heart

Question 33

what type of molecule is noreadrenaline

Answer 33

neurotransmitter

Question 34

what type of molecule is adreneline

Answer 34

hormone

Question 35

what is the general structure of catecholamines

Answer 35

catechol group | alkylamine group

Question 36

what are the lead chemical messengers in the adrenic system

Answer 36

noreadrenaline, adrenaline

Question 37

what functional groups are on catecholamines

Answer 37

phenol (meta and para), alcohol, protonated amine

Question 38

how do phenol groups of catecholamines work

Answer 38

form H-bonds to binding site (especially B-adrenoreceptors) | meta-phenol can be replaced with other hydrogen bonding groups

Question 39

how do alcohol groups of catecholamines work

Answer 39

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

Question 40

how do protonated amine groups of catecholamines work

Answer 40

forms an ionic interaction with the binding site

Question 41

how does the N-alkyl group of catecholamines work

Answer 41

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

Question 42

how does the aromatic ring group of catecholamines work

Answer 42

forms Van der Waals interactions with the binding site

Question 43

what are the features of an adrenic binding site

Answer 43

hydrophobic pocket in B-receptors

Question 44

what are the features of isoprenaline

Answer 44

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

Question 45

what are the features of isoetharine

Answer 45

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

Question 46

what are the features of salbutamol

Answer 46

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))

Question 47

what does SAMA stand for

Answer 47

short acting muscarinic antagonist

Question 48

what is an example of a SAMA

Answer 48

ipratropium

Question 49

what does SABA stand for

Answer 49

short acting beta-2 agonist

Question 50

what is an example of a SABA

Answer 50

salbutamol