Noradrenaline Agonists and Antagonists

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  • Created by: LBCW0502
  • Created on: 23-10-18 09:06
Which drug has a highly toxic stereoisomer?
Thalidomide - previous used in pregnancy (S-isomer, toxic)
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Which King's scientist won a Nobel Prize for his discovery of the world's first beta blocker?
James Black
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What type of receptor does ATP bind to?
Ion channels
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What are the two types of core structure ?
Sympathomimetic amine core (aromatic - CH-CH-NH) and catecholamine core (catechol hydroxyls - CH-CH-NH)
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Which neurotransmitter contains the sympathomimetic amine core?
Serotonin (5HT)
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Which neurotransmitters contain the catecholamine core?
Noradrenaline and dopamine
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Outline features of stereoisomerism (R vs S) - 2D and 3D structures
Chiral carbon, prioritize groups based on atomic number (1-highest, 4-lowest). Clockwise (R), anti-clockwise (S). Spatial arrangement determines different properties and interactions with receptor (only one stereo-isomer will bind to receptor)
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Describe features of the adrenaline pharmacophore
Catechol hydroxyls, chiral aliphatic hydroxyl group (R-configuration), 2C chain, amine/hydroxymethyl, basic amino function and N-substitution (A and NA differ by methyl group/variable group)
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Describe how noradrenaline binds to the active site of a receptor
H bonding for Ser residues/catechol hydroxyls, electrostatic interactions/NH3+/Asp residue, H bonding with catechol hydroxyls/Asn residue. H bonding with OH and Ser in pocket (R-form), Phe/Trp pi-pi stacking/hydrophobic interactions
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Describe features of alpha and beta selectivity
NA: R=H, a>b, need 4-OH. A: R=Me, b>a. Isoprenaline: R=CH(Me)2, only b activity, short acting (20 mins) due to high COMT metabolism. Bigger N-substituted groups lead to b>a
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Why do bulkier N-substituted groups increase agonist/antagonist binding to the receptor?
Stronger interactions with residues in the active site of the receptor e.g. hydrophobic interactions, pi-pi stacking - keeps molecule in place
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Describe the chemical structure of salbutamol
B2 selectivity, 3-OH groups, NH, (CH3)3 groups - agonist
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Describe the chemical structure of propranolol
Non-specific beta antagonist. Aromatic system, ether, OH, NH and (CH3)2 groups
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Modification of which group can increase beta 2 selectivity?
3-OH. Isoproterenol (low selectivity for beta 2). Soterenol (sulfonamide, b2 selective increases). Salbutamol (hydroxymethl, b2 selectivity increases). Other examples, aminomethyl, fused ring - 1 OH can be accommodate at 4 position on aromatic ring
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When making modifications to chemical structures what must be replaced?
The interaction which OH would produced must be replaced by a different interaction e.g. electrostatic interaction from amine group
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Describe the effect of bulky N-alkyl groups on beta 2 selectivity
Bulky N-alkyl groups increase beta 2 selectivity (e.g. NA, salbutamol)
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How do bulky N-substituents affect the off rate?
Bulky N-substituents decrease off rate (amount of time off receptor/spends more time bound to receptor). E.g. Severent (bronchodilator acts on b2 receptors, treat asthma, lasts 12h, low off-rate, longer lasting effect)
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Which groups can be inserted into structures to increase beta 1 selectivity?
Hydroxylmethyl groups between aryl and hydroxyl groups
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Describe features of beta antagonists - catechol ring
Catechol ring can be replaced by other ring systems (interact with Trp/Tyr, lack of 3/4 OH removes agonist activity)
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Describe features of beta antagonists - side chain
Side chain must contain hydroxyl for antagonist function (hydroxy/methoxy groups form H bonds with Asn)
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Describe features of beta antagonists - N-substituents
N-substituents must be bulky for activity (electrostatic interactions with Asp, increase affinity for receptor like b-agonists)
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Describe features of early-agonist therapy
Adrenaline used to treat asthma after WWII. Severe side effects (increase bp/HR/stimulation of a/b receptors). Led to development of b-specific agonists. Isoprenaline (short acting/20mins, high COMT metabolism, palpitations, longer acting one needed)
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Describe features of salbutamol
First marketed in 1960s, best-selling asthma drug on market, longer acting than isoprenaline (4hrs)
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Describe features of salmetarol
Longer-lasting analogue of salbutamol (1980s) - 12hrs. Marketed as Serevent (Glaxo), taken BD, used for ongoing treatment of asthma (salbutamol still used for rapid relief of acute attacks)
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Describe features for formulating salbutamol and salmetrarol
Salbutamol (200 mcg/dose but only 2-3% absorbed). Salmetarol (inhalation, 50mcg/dose). High use of b-agonists (> 2 cans/month) not appropriate as sole therapy in severe/unstable asthma. Stabilised with inhalation glucocorticosteroids
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Describe the development of beta blockers
Used to treat cardiovascular disease. Blockage of b-receptors results in reduced bp/HR. DCI (1950s) - b-agonist activity, specific b-antagonist required
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What would be the main side effect of b-agonist activity of DCI?
Reduced blood pressure and reduced heart rate
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Describe features of pronethalol
First commercially successful b-blocker (1960s, James Black - nobel prize for development of b-blockers). Led to discovery of propranolol
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What are the dosing considerations for beta blockers?
Cardiovascular specificity (high b1 selectivity). Low lipid solubility (reduction in side effects). High half-life (increased efficacy)
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Describe features of asthma morbidity (1)
Deaths due to asthma increase. Associated with long term b-agonist use. Inadequate use of glucocorticosteroids. B-agonist - hyper-responsiveness to agents which stimulate asthma e.g. inhaled histamine, excessive tissue repair (scar tissue formation)
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Describe features of asthma morbidity (2)
People with asthma have bronchioles with tight smooth muscle, extra mucus produced (trap particulates). Alveoli trapped with air. Inflammed airway - could lead to COPD (alveoli burst)
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Describe features about the toxicity of beta blockers
Decrease glucose intolerance, increased hyperlipidaemia, use of b-blockers contraindicated for asthma suffers (breathing problems/bronchoconstriction). Propranolol/metoprolol cross BBB, results in CNS effects (dizziness, increased sedation)
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Card 2

Front

Which King's scientist won a Nobel Prize for his discovery of the world's first beta blocker?

Back

James Black

Card 3

Front

What type of receptor does ATP bind to?

Back

Preview of the front of card 3

Card 4

Front

What are the two types of core structure ?

Back

Preview of the front of card 4

Card 5

Front

Which neurotransmitter contains the sympathomimetic amine core?

Back

Preview of the front of card 5
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