MD1: SAR of B-Agonists & Antimuscarinics Flashcards
what do salbutamol and ipratropium treat
symptoms of asthma and chronic obstructive pulmonary disease
what does COPD stand for
chronic obstructive pulmonary disease
what is the duration of onset of salbutamol
short-term relief due to short onset
what is the duration of onset for ipratropium
short-term relief due to short onset
what are two examples of short duration of action bronchodilators
salbutamol, ipratropium
what modifications can be made to convert lead compounds into selective agonists or antagonists
chain extension, conformational restriction, group shifting, chiral switching
where are lead compounds found
natural receptor ligands like acetylcholine and noradrenaline collections of synthetic compounds existing drugs natural products like muscarine computer aided rational design
what are the features of the SAR on acetylcholine
the ester group (acetyl)
the nitrogen group (choline)
CH2-CH2 between ester and nitrogen group is needed
what structural features would not be tolerated when considering the SAR of acetylcholine
large esters
CMe3 instead of NMe3
what are the overall conclusions of SAR for acetylcholine
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
how many variations of ACh are there
many
due to several freely rotatable single bonds
what are the two types of cholinergic receptor
nicotinic and muscarinic
what type of activity do cholinergic receptor types have
agonist
where are the receptors located that nicotine works on
cholinergic receptors at nerve synapses and skeletal muscle
where are the receptors located that L+-muscarine works on
cholinergic receptors on smooth and cardiac muscle
why are muscarine and nicotine rigid ACh analogues
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
what are the natural product leads in the development of cholinergic antagonists (muscarine)
atropine and hyoscine
what are the important binding groups in atropine and acetylcholine
amine and ester groups use ionic and H-bonding
the position of these groups is similar in both molecules
what group in atropine and acetylcholine needs to be protonated when bound to a receptor
nitrogen
how does atropine bind to receptors
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
what receptors do synthetic cholinergic antagonists work on
muscarinic receptors
what are two examples of synthetic cholinergic antagonists
ipratropium and atropine methonitrate
what does atropine methonitrate do
lowers GI motility
what does ipratropium do
bronchodilator
what happens to synthetic cholinergic antagonist analogues
they are fully ionised and unable to cross the blood brain barrier
they have no CNS side effects
what are the important r]features of muscarinic receptor antagonists
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
what is the function of branching on aromatic/heteroaromatic rings of muscarinic receptor antagonists
they allow extra hydrophobic binding regions available next to normal ACh binding site
what is the effect of activating a-adrenoreceptors
contraction of smooth muscle (except the gut)
what is the effect of activating B2-adrenoreceptors
relaxing smooth muscle
what is the effect of activating B1-adrenoreceptors
contracting cardiac muscle
where do B2-adrenoreceptors predominate
the airways
where do B1-adrenoreceptors dominate
the heart
what type of molecule is noreadrenaline
neurotransmitter
what type of molecule is adreneline
hormone
what is the general structure of catecholamines
catechol group
alkylamine group
what are the lead chemical messengers in the adrenic system
noreadrenaline, adrenaline
what functional groups are on catecholamines
phenol (meta and para), alcohol, protonated amine
how do phenol groups of catecholamines work
form H-bonds to binding site (especially B-adrenoreceptors)
meta-phenol can be replaced with other hydrogen bonding groups
how do alcohol groups of catecholamines work
forms a hydrogen bond to the binding site (R-enantiomer more active)
how do protonated amine groups of catecholamines work
forms an ionic interaction with the binding site
how does the N-alkyl group of catecholamines work
affect target selectivity; larger N-alkyl groups lead to selectivity for B-adrenoreceptors
how does the aromatic ring group of catecholamines work
forms Van der Waals interactions with the binding site
what are the features of an adrenic binding site
hydrophobic pocket in B-receptors
what are the features of isoprenaline
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
what are the features of isoetharine
shows selectivity for B2-adrenoreceptors
ethyl group introduces B2-selectivity
short lasting due to drug metabolism
metabolised by catechol-O-methyltransferase
what are the features of salbutamol
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))
what does SAMA stand for
short acting muscarinic antagonist
what is an example of a SAMA
ipratropium
what does SABA stand for
short acting beta-2 agonist
what is an example of a SABA
salbutamol
