Beta Blockers Flashcards
Which 2 types of NS does the peripheral NS utilise?
Cholinergic
Adrenergic
What does the cholinergic use?
Ach
What does adrenergic use?
Adrenaline + noradrenaline
What is adrenaline?
Hormone
What are noradrenaline + Ach?
Neurotransmitters
What are the 2 types of adrenoreceptors?
G-protein coupled receptors
Alpha - 1,2
Beta - 1,2,3
Describe beta receptor
7TM receptor
G protein linked to adenyl cyclase
= ATP to cAMP
Protein phosphorylation drives response
What are the structures of adrenaline + noradrenaline?
Small + simple molecules
Catechol ring
Alkylamine chain
Stereogenic centre
Describe the adrenergic binding sites
Pi-Pi stacking of Van der Waals
H bonding
Catechol H bonding
Hydrophobic interactions
What are the important binding groups?
OH
Ring
NHR2
Why should it be a R stereoisomer?
More reactive than S
= orientation different
What does it mean if the R2 is larger on the NH?
Larger = increased beta selectivity
What are molecules that won’t bind?
Tyramine = missing OH
Amphetamine = CH3 pushed NH2 too far out
What was pronethalol found to do?
Block beta receptors + partial agonist
Why was pronethalol withdrawn?
Toxicology concerns
Describe propranolol structure
Linking group
Dual benzene ring
What are epoxides?
Strained 3-membered rings
Strong Nu under basic conditions
What is epichlorohydrin?
“Special” epoxide for providing a 1,2,3-substituted compound
What were the side effects of 1st generation beta blockers?
Crossed BBB = dizziness/sedation
Bronchoconstriction = asthmatics
Lowered CO
What were the issues with propranolol?
High logP
= hydrophobic
= BBB penetration
How to fix propranolol?
Reduce logP
= take out 1 aromatic ring
What was the 2nd generation?
Practolol
= not as potent BUT more selective
Why was practolol withdrawn?
Rashes, eye problems + peritonitis
How were 2nd generation modified?
Contained extended para substituent
How were short-acting beta blockers created?
Amides resistant to hydrolysis
So ester instead
= esmolol
How were 3rd generation created?
Incorporate + extend amine substituent with proposal interact with another part of beta 1 receptor
What are examples of 3rd generation?
Primidolol
Epanolol
What are examples of 2nd generation?
Atenolol
Betaxolol
