Chemistry Flashcards
Adrenaline
chiral molecule
hormone & neurotransmitter
controls: heart rate, blood vessel diameters, air passage diameter, metabolism
Adrenaline chemical structure
phenyl group with 2 hydoxyls, alkyl side chain with a hydroxyl group terminated with a secondary amine
mono-amine, family: catecholamine
Catecholamine
1,2-dihydroxybenzene
Adrenaline as a drug
agonist, treatment for anaphylaxis
reason: very fast treatment
Auvi-Q, epipen
Noradrenaline
replace N-mthyel with N-H
Potency
Adrenaline: same for alpha and beta
NA: greater potency for alpha
Adrenaline Biosynthesis
- L-Tyrosine (from food) + Tyrosine hydroxylase –> Levodopa (treating Parkinson’s)
- Levodopa + Dopa decarboxylase –> Dopamine (pleasure sensation in the brain)
- Dopamine + Dopamine β-hydroxylase –> Noradrenaline
- Noradrenaline + N-methyltransferase –> Adrenaline
Adrenoceptors types
β1: increase heart rate, renin secretion from kidneys
β2 receptors: relax bronchi, stimulate insulin release, inhibit histamine release from mast cells
Isoetharine
3rd generation
ultra-short acting
β2 selectivity obtained by:
- introducing alkyl substituents to the side chain linking aromatic ring and amine group
- varying the alkyl substituents on the N atom
Ultra-short acting (<3 hrs) due to:
Taken up by tissues and mutilated by the enzyme catechol-O-methyl-transferase (COMT) to form an inactive metabolite
Fix:
Replaced meta-OH with -CH2OH –> more resistant to metabolism
Isoprenaline non-specificity
Isoprenaline, acts on β1 (heart) & β2 (bronchi) –> mortality epidemic
Discovered when small doses given to hypoxemic dogs. Hypoxemia is common is asthmatic patients.
Salbutamol is 7 times less potent in raising heart rate in humans
Isoprenaline non-specificity
Isoprenaline, acts on β1 (heart) & β2 (bronchi) –> mortality epidemic
Discovered when small doses given to hypoxemic dogs. Hypoxemia is common is asthmatic patients.
Salbutamol is 7 times less potent in raising heart rate in humans
Fenoterol
short-acting β2 agonist
can activate β1 receptors at doses higher than recommended
withdrawn from NZ due to mortality issues thought to be due to excessive usage for severe asthma attacks in absence of medical assistance, up to 80 puffs before seeking medical attention
Adrenoreceptors SAR
Important features:
- configuration at stereocentre where only R stereoisomer most effective
- Bigger R group at amine group favours β selectivity over α
- R group plays role in β2 selectivity and duration of action
- meta OH at phenyl ring causes bioavailability issues due to metabolism by COMT, largely fixed when replaced by -CH2OH
- para phenolyc hydroxyl group plays a role in β vs α selectivity. Removal of the hydroxyl causes the molecule to favour α receptors. over β receptors
Salbutamol
short-acting (4-6 hours)
same potency as isoprenaline but less active on the heart
meta-CH2OH group –> longer duration and more resistant to metabolism by COMT
bulky tert-butyl group at amine:
- reach and form additional interactions wiht non-polar region in the binding site
- produces selectivity for β2 receptors
salbutamol enantiomers
R enantiomer is more active but marketed it as a racemate becuase S blocks the metobolism of R
Salmeterol
treatment of nocturnal asthma (arnd 4 am)
increased length of the N-alkyl substituent with a hydrocarbon chain and aromatic ring:
-increased lipophilicity to bind more strongly to tissue in the vicinity of the adrenoreceptors –> longer duration of action (2x longer than salbutamol, 12 hours)
R enantiomer more active
meta-CH2OH –> higher bioavailabilty
bulky R-group: β2 selectivity & higher lipophilicity
Salmeterol vs Salbutamol
slower onset of action due to:
initially diffuse into plasma membrane of lung cells and
slow release back outside the cell to receptors –> suitable for prevention rather than relief of asthma attacks
-longer duration of action due to:
accumulate in plasma membrane then release over time to receptors–> nocturnal asthma
SAR
Structure-Activity Relationship
Steroids structure
- Based on ‘gonane’ nucleus
- 19/20 carbons
- 4 fused rings: 3 6-membered, 1 5-membered
- 2 methyl group at C-10 and C-13 (A-B junction and C-D junction)
- alcohol side chain at C-17
- most naturally occuring steroids: 5-alpha gonane /5-beta gonane types –> referring to orientation of hydrogen atom at C-5
Steroids in humans
- sex hormones (testosterone, estrogen, progesterone
- cholesterol: essential component in cell membranes to establish permeability and fluidity of cell membranes
- corticosteroids: steroid hormones that are not sex hormones, can be classifed as:
glucocorticoids: metabolism, stress response, immune response and inflammation, present in almost in every mammal cell
mineralocorticoids: renal and blood function, water and electrolyte balance
Steroids as meds
- arthritis
- contraception
- asthma
- anabolic steroids for strength building (often illicit)
Cortisone
21 carbon glucocorticoid
released in reaction to stress
released with adrenaline and elevate blood pressure to prep for fight or flight response
Cortisone as a med
- suppress immune system (immune diseases and organ transplants)
- anti-inflammatory (arthritis)
- increase blood sugar (care with diabetes)
Corticosteroids and arthritis
- cortisone
- prednisone
- methylprednisolone
- systemically or direct injection into joint
- often a particulate suspension –> can re-crystallise in join after injection –> inflammation in the surrounding tissue and pain worse than before the shot
Steroids and asthma
- reduce inflammation within bronchio tubes
- inhaled as aerosol/spray or taken orally as tablets (ex: prednisone), vein injections for severe symptoms
Steroids stereochemistry
- badge (thick bond/above ring) –> denoted as β
- dotted bond (below ring/into page) –> denoted as α
-naturally occurring steroids: all 4 rings in chair formation
- B-C ring junction tans
- C-D ring junction almost always trans
-A-B ring junction can be trans or cis:
trans –> H at C-5 is α oriented –> colestanes
cis –> H at C-5 is β oriented –> coprostanes
- stereochemically rigid (cannot change conformation without breaking bonds)
Physical properties of steroids
- stable compounds
- white crystalline solids
- mp 100-250 c
- poorly soluble in water, ok in ethanol and organic solvents (due to high hydrocarbon percentage)
Cholestrol
sterol: hydroxyl group at C-3
- precurosr for all steroid hormones, bile acids and vit D
- 30-50g cholestrol in human body
- 37 steps of biosynthesis
Cholestrol –> Pregnenolone
- Cholestrol oxidised into dihydroxylated intermediate
- intermediate undergoes oxidative cleavage to form pregnenolone with ketone side chain
- isocarproic acid as side product
Pregnenolone –> other steroids
- oxidation of C-3 hydroxyl group to a ketone function
- β - γ and saturated ketone function will undergo 2-step enzymatic catalysed isomerisation to give α - β unsaturated system in progesterone
Keto-enol tautomerisation
acid-catalysed tautomerisation
base-catalysed
