Chemistry

Question 1

Adrenaline

Answer 1

chiral molecule
hormone & neurotransmitter
controls: heart rate, blood vessel diameters, air passage diameter, metabolism

Question 2

Adrenaline chemical structure

Answer 2

phenyl group with 2 hydoxyls, alkyl side chain with a hydroxyl group terminated with a secondary amine

mono-amine, family: catecholamine

Question 3

Catecholamine

Answer 3

1,2-dihydroxybenzene

Question 4

Adrenaline as a drug

Answer 4

agonist, treatment for anaphylaxis
reason: very fast treatment

Auvi-Q, epipen

Question 5

Noradrenaline

Answer 5

replace N-mthyel with N-H

Question 6

Potency

Answer 6

Adrenaline: same for alpha and beta

NA: greater potency for alpha

Question 7

Adrenaline Biosynthesis

Answer 7

1. L-Tyrosine (from food) + Tyrosine hydroxylase –> Levodopa (treating Parkinson’s)
2. Levodopa + Dopa decarboxylase –> Dopamine (pleasure sensation in the brain)
3. Dopamine + Dopamine β-hydroxylase –> Noradrenaline
4. Noradrenaline + N-methyltransferase –> Adrenaline

Question 8

Adrenoceptors types

Answer 8

β1: increase heart rate, renin secretion from kidneys

β2 receptors: relax bronchi, stimulate insulin release, inhibit histamine release from mast cells

Question 9

Isoetharine

Answer 9

3rd generation
ultra-short acting

β2 selectivity obtained by:

1. introducing alkyl substituents to the side chain linking aromatic ring and amine group
2. 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

Question 10

Isoprenaline non-specificity

Answer 10

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

Question 11

Isoprenaline non-specificity

Answer 11

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

Question 12

Fenoterol

Answer 12

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withdrawn from NZ due to mortality issues thought to be due to excessive usage for severe asthma attacks in absence of medical assistance, up to 80 puffs before seeking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

Question 13

Adrenoreceptors SAR

Answer 13

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

Question 14

Salbutamol

Answer 14

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

Question 15

salbutamol enantiomers

Answer 15

R enantiomer is more active but marketed it as a racemate becuase S blocks the metobolism of R

Question 16

Salmeterol

Answer 16

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

Question 17

Salmeterol vs Salbutamol

Answer 17

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

Question 18

SAR

Answer 18

Structure-Activity Relationship

Question 19

Steroids structure

Answer 19

• 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

Question 20

Steroids in humans

Answer 20

• 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

Question 21

Steroids as meds

Answer 21

• arthritis
• contraception
• asthma
• anabolic steroids for strength building (often illicit)

Question 22

Cortisone

Answer 22

21 carbon glucocorticoid

released in reaction to stress

released with adrenaline and elevate blood pressure to prep for fight or flight response

Question 23

Cortisone as a med

Answer 23

• suppress immune system (immune diseases and organ transplants)
• anti-inflammatory (arthritis)
• increase blood sugar (care with diabetes)

Question 24

Corticosteroids and arthritis

Answer 24

• 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

Question 25

Steroids and asthma

Answer 25

- reduce inflammation within bronchio tubes | - inhaled as aerosol/spray or taken orally as tablets (ex: prednisone), vein injections for severe symptoms

Question 26

Steroids stereochemistry

Answer 26

- 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)

Question 27

Physical properties of steroids

Answer 27

- stable compounds - white crystalline solids - mp 100-250 c - poorly soluble in water, ok in ethanol and organic solvents (due to high hydrocarbon percentage)

Question 28

Cholestrol

Answer 28

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

Question 29

Cholestrol --> Pregnenolone

Answer 29

1. Cholestrol oxidised into dihydroxylated intermediate 2. intermediate undergoes oxidative cleavage to form pregnenolone with ketone side chain 3. isocarproic acid as side product

Question 30

Pregnenolone --> other steroids

Answer 30

1. oxidation of C-3 hydroxyl group to a ketone function 2. β - γ and saturated ketone function will undergo 2-step enzymatic catalysed isomerisation to give α - β unsaturated system in progesterone

Question 31

Keto-enol tautomerisation

Answer 31

acid-catalysed tautomerisation | base-catalysed