Adrenaline chemistry Flashcards
What are adrenaline’s effects on the body and what family does it belong to?
- Increases heart rate, blood vessel diameter, airway diameter and metabolism
- Of the catecholamine family (mono-amine)
What is adrenaline?
- A hormone/neurotransmitter
- Fight or flight response
How does noradrenaline differ from adrenaline and what effect does this have?
Noradrenaline (NT of the body) features a hydrogen bound to the amine instead of a methyl group in adrenaline.
This conveys much more specific action, activating α-adrenoceptors.
What are the steps in adrenaline biosynthesis and what enzymes are involved?
- L-tyrosine (amino acid) (tyrosine hydroxylase) - L-DOPA (L-dihydroxyphenylalanine) (DOPA decarboxylase) (Aromatic L-amino acid decarboxylase) - Dopamine (Dopamine beta-hydroxylase) - Noradrenaline (Phenylethanolamine) (N-methyltransferrase; transferring methyl onto amine instead of hydrogen)
What do α-1 adrenoceptors activate?
Smooth muscle contraction (often vasoconstriction in blood vessels e.g. -skin, -GI system, -renal artery, -brain) via release of Ca2+ etc.
(vascular smooth muscle contraction)
What do α-2 adrenoceptors activate?
- Inhibits insulin release
- Inhibits noradrenaline release in brain and CNS
- Contraction of sphincters in GI tract.
(vascular smooth muscle contraction, pre-junctional regulation of NA release)
What do β-1 adrenoceptors activate?
- Increase heart rate
- Renin (an angiotensinogenase) secretion from kidney
(SA node and ventricles in heart; rate and force of contraction)
What do β-2 adrenoceptors activate?
- Relaxes bronchi
- Stimulates insulin release
- Inhibits histamine release from mast cells (allergies)
(airway smooth muscle relaxation)
What do β-3 adrenoceptors activate?
- Enhances lyopolysis in adipose (fatty) tissue etc
skeletal muscle, adipose tissue
Is adrenaline selective?
No; it is an agonist for both α and β receptors.
noradrenaline is agonist for just α
What structural change from adrenaline brings about α-selectivity? (and name a subsequent drug)
- Removing the bottom -OH group on the aromatic ring,
e. g. phenylephrine.
What structural change from adrenaline brings about β-selectivity? (and name a subsequent drug)
- Amine substitution (the 2 hydrogens from initial methyl group and both replaced with more methyl groups)
e. g. isoprenaline
What structural change from adrenaline brings about short-lasting β-2 selectivity? (and name a subsequent drug)
- Substitution of hydrogen between OH and N for butyl group
e. g. isoetharine
What structural change from adrenaline brings about longer-lasting β-2 selectivity? (and name a subsequent drug)
- Addition of CH2 between top -OH on aromatic ring and the aromatic ring
- Bulkier N-substituent (more lipophilic as a result; bigger R-group attached favours β-2 selectivity; T-butyl group in…)
e. g. salbutamol
Why is the β-2 selective agonist isoetharine so short-lasting?
- Taken up by tissues and methylated by COMT (Catechol-O-methyltransferase) to inactive form
(thus replacing -OH with CH2OH yields greater resistance to metabolism)
Why is salbutamol #preferable to isoprenaline to treat bronchoconstriction?
- Salbutamol acts just on the β-2 adrenoceptors
- Isoprenaline acts on β-1 and β-2; gave rise to a mortality epidemic when small doses given to hypoxemic dogs (asthma sufferers would have low O2 too…) giving rise to fatal cardiac depression.
- Salbutamol is 7 times less potent than isoprenaline in raising heart rate in humans.
Why was the short-acting β-2 agonist fenoterol withdrawn from the market?
- Short-acting β-2 agonist also stimulated β-1 when used above recommended dose (possible abuse of dose during bronchoconstriction)
- Thus withdrawn from market (NZ) due to mortality issues
Why is salbutamol given as a racemic mixture?
- R-stereoisomer is active form
- However S-form actually blocks metabolism of R-form thus lasting longer
- Thus giving S with R enhances activity of R
What are the steps of Salbutamol synthesis?
- Fries re-arrangement
- Esterification
- Bromination
- Nucleophilic substitution
- Reduction
- Hydrogenolysis
How does Salmeterol achieve its long-acting status?
- Bulky N-substituent (alkyl tail w/ester/benzene ring)
- Thus more lipophilic (hangs on for longer?)
- Acts for 2x longer than salbumatom
