HEENT 04: Chemistry of Adrenergic Agonists/Antagonists Flashcards
α1 (Post-synaptic) Receptor
- Gq/11-coupled
- agonist
- decongestant
α2 (Pre-synaptic) Receptor
- Gi-coupled
- agonist
- glaucoma
𝝱1 (Post-synaptic) Receptor
- Gs-coupled
- antagonist
- glaucoma
Determine what structural modifications to the phenylethanolamine scaffold drives adrenergic receptor selectivity, as well as involves direct and indirect activities.
- C-1 hydroxyl must be in (R)-absolute configuration for maximal direct activity for 3-point attachment to ꞵ-adrenergic receptor
- positively charged (pKa 8.5-10) – basic
- substituents determine receptor selectivity and duration of action – R1 and R2: commonly alkyl groups, R3: typically combination of hydroxyl substitutions
What is phenylethanolamine required for?
high agonist activity
How are α and ꞵ-adrenergic receptors originally classified?
based on agonist response in ↓ order of potency:
- α: epinephrine > norepinephrine > isoproterenol
- ꞵ: isoproterenol > epinephrine ≥ norepinephrine
What are catecholamines?
natural adrenergic receptors agonists
- norepinephrine
- epinephrine
Describe the selectivity of catecholamines.
non-selective
- interact with all adrenergic receptor subtypes (α1, α2, ꞵ1)
- rapidly cleared in blood (t1/2 = 2 min)
What is monoamine oxidase (MAO)?
mitochondrial, membrane-bound flavin-containing enzyme that catalyzes oxidative deamination of monoamines
- R-CH2-NH2 + O2 → [R-CH=NH] → R-CHO + NH4
What is catechol O-methyltransferase (COMT)?
soluble and membrane-bound enzyme that transfers methyl group from S-adenosyl-L-methionine to catechol hydroxyl group (more commonly at 3 position over 4)
Explain how modifications to adrenergic receptor agonists impact metabolism by COMT and/or MAO.
–
When R1 is Methyl Group
- α and ꞵ-adrenergic receptor activity is maximal
- BUT isopropyl group eliminates α activity and slows down MAO metabolism of drug
- epinephrine: ꞵ ≥ α
- isoproterenol: general ꞵ
When R1 is t-butyl Group
can achieve ꞵ2 selectivity
- colterol: selective ꞵ2
Substitutions at R2
- reduce or eliminate MAO activity
- introduce stereocenter at C-2 that influences receptor binding
3’, 4’-diOH Compounds:
- poor oral bioavailability – rapidly metabolized by COMT
- shifting hydroxyl positions can impact selectivity and improve oral bioavailability
- isoproterenol: general ꞵ
- metaproterenol: selective ꞵ2
When R3 is 3’OH
can achieve α1-adrenergic receptor selectivity at expense of any ꞵ activity
- metaraminol: selective α1
- metaproterenol: selective α
When R3 is H Atom
(phenyl ring is devoid of phenolic substituents)
can exhibit both direct and indirect activities
- ephedrine/pseudoephedrine: α + ꞵ
- phenylpropanolamine: α + ꞵ
What is phenylephrine?
α1-selective adrenergic receptor agonist that causes vasoconstriction – decongestant
What is (1R,2S)-ephedrine?
most potent structural isomer
- elicits mixed acting response (direct and indirect adrenergic receptor activity) on α and ꞵ-receptors
What is (1S,2R)-ephedrine?
primarily indirect activity
What is (1S,2S)-pseudoephedrine?
primarily indirect activity
- less CNS side effects than ephedrine
- used as decongestant in enantiomerically pure form
- pure form required to yield CNS stimulant (S)-methamphetamine
What is (R)-methamphetamine (levomethamphetamine)?
sympathomimetic vasoconstrictor in some OTC decongestants (inhalers)
What is (S)-methamphetamine?
non-polar and lipophilic characteristics allows to cross BBB for CNS effects
Recognize and distinguish the alpha-2-selective adrenergic receptor agonists brimonidine and apraclonidine.
–
What are 2-aminoimidazolines (α2-selective drugs)?
stimulate α2-adrenergic receptors in eye to reduce intraocular pressure with minimal effects on cardiovascular and pulmonary parameters
- apraclonidine
- brimonidine
What does apraclonidine do?
reduction of aqueous humour formation
What does brimonidine do?
reduction of aqueous humour formation and increase in uveoscleral outflow
- 1000x more selective for α2 than α1 receptors
- more selective and clonidine and apraclonidine
Identify the general structure and important features (ie. oxymethylene bridge) of beta-adrenergic receptor antagonists (beta-blockers).
- oxymethylene bridge: bridging group inserted into pronethalol to create non-selective ꞵ-blocker propranolol
- stereochemistry – nomenclature changes due to insertion of oxygen atom, which changes Cahn-Ingold-Prelog priority assignments
- lipophilicity: logP correlates with ability to enter CNS and with primary site of clearance – lipophilic drugs are cleared by liver, more hydrophilic agents are cleared by kidney
1st Generation ꞵ-Blocker for Glaucoma
non-selective ꞵ-adrenergic antagonists
- propanolol
- levobunalol
- timolol
2nd Generation ꞵ-Blocker for Glaucoma
selective ꞵ1-adrenergic antagonist
- betaxolol
- decrease intraocular pressure by inhibiting formation of aqueous humour
- contraindicated with MAO inhibitors – like other ethanolamine compounds
