PHA6142: Organic Medicinals

Catecholamines and non-catecholamines

What are the two major structural classifications of adrenergic agonists?

Ethylamine chain

What is the essential chain for adrenergic agonist activity?

Appropriate substituents on the benzene ring

What structural feature makes a phenylethylamine a direct adrenergic agonist?

3,4-dihydroxy

What aromatic substitution pattern characterizes a catechol?

β-OH

Which group on the ethylamine portion is important for adrenergic agonist activity?

β-receptor affinity increases

What happens when the N-substituent becomes larger in phenylethylamine adrenergic agonists?

H or CH3

Which N-substituent favors α-receptor activity?

Isopropyl

Which N-substituent strongly favors β-receptor activity?

tert-Butyl

Which N-substituent is associated with β2 selectivity?

α activity

Removal of the para-OH from a catecholamine generally leaves which activity?

Meta-OH

Which aromatic OH is essential for direct α and β activity?

COMT metabolism and MAO oxidative deamination

Why do catecholamines have short duration of action?

COMT

What enzyme methylates the catechol ring?

Resorcinol

What structural ring is resistant to COMT and therefore tends to increase oral activity and duration?

tert-Butyl N-substituent

Which structural feature of salbutamol increases β2 selectivity?

Replace catechol meta-OH with CH2OH

What structural change improves oral bioavailability of salbutamol?

Epinephrine

Which drug is a nonselective α/β adrenergic agonist?

Isoproterenol

Which drug is a nonselective β agonist containing a catechol and N-isopropyl group?

Phenylephrine

Which drug is an α1-selective agonist with one aromatic OH?

Dobutamine

Which drug is a β1-selective agonist with a catechol and a large N-substituent?

Salbutamol and terbutaline

Which drugs are classic β2-selective non-catechol agonists?

Ar–X–imidazoline

What is the key structural feature of imidazoline α-agonists?

It tends toward antagonist activity

What happens when an imidazoline agonist contains two aromatic rings?

Xylometazoline

Which drug is an imidazoline α agonist derived from xylene?

Naphazoline

Which imidazoline α agonist contains a naphthalene ring?

Tetrahydrozoline

Which drug contains tetralin + imidazoline?

Clonidine

Which α2 agonist has an Ar–NH–imidazoline structure?

Methyldopa

Which α2 agonist is a phenylethylamine derivative with an α-methyl group?

α-methyl group

Which structural modification increases indirect sympathomimetic activity?

Lipophilicity increases

What happens when the number of carbons increases in an indirect sympathomimetic?

Amphetamine > Ephedrine > Phenylpropanolamine

Which is the correct order of lipophilicity?

OH

Which group generally increases direct adrenergic agonist activity?

Haloalkylamine

What is the characteristic structural class of phenoxybenzamine?

Irreversible nonselective α blocker

What type of α blocker is phenoxybenzamine?

Reversible nonselective α blocker

What type of α blocker is phentolamine?

Quinazolines

Which structural class contains prazosin, terazosin, and doxazosin?

Quinazoline + piperazine + acyl moiety

What three major structural components characterize prazosin-like α1 blockers?

4-amino group

Which group is essential for α1 affinity in quinazoline blockers?

Yohimbine

Which α blocker is a naturally occurring indole alkaloid?

Arylethanolamines and aryloxypropanolamines

What are the two major structural classes of β blockers?

O–CH2 bridge

What structural bridge distinguishes aryloxypropanolamines?

Propranolol

What is the prototype first-generation nonselective β blocker?

Naphthalene

What aromatic system is present in propranolol?

S(+)

Which stereoisomer of propranolol is much more active?

Ether and alcohol

What is essential for β-blocker receptor binding in the aryloxypropanolamine structure?

Para substitution

What type of aromatic substitution tends to produce β1 selectivity?

To allow extra H-bonding interaction favoring β1

Why are second-generation β blockers para-substituted?

Propranolol

Which β blocker is contraindicated in asthma because it blocks β2 receptors?

Adrenergic β blockers

Which class of β blockers generally ends in -olol?

Quaternary ammonium

What is the essential nitrogen feature of acetylcholine?

2

How many carbons should separate the quaternary nitrogen from the ester in acetylcholine analogs?

Ester

Which functional group is important in acetylcholine activity?

At least two methyl groups on quaternary nitrogen

Which nitrogen substitution is optimal in acetylcholine?

Activity decreases

What happens when the acetoxy methyl group is extended?

Methacholine

Which choline ester is three times more stable than acetylcholine?

S

Which enantiomer of methacholine is more active?

NH2 replaces CH3 of the carbamoyl group

What structural change makes carbachol resistant to hydrolysis?

Bethanechol

Which cholinergic agonist is the most stable among acetylcholine, methacholine, carbachol, and bethanechol?

Bethanechol

Which cholinergic agonist is orally active and muscarinic selective?

Carbachol

Which cholinergic agonist is used topically for glaucoma?

Pilocarpine

Which muscarinic alkaloid has a tertiary amine?

Muscarine

Which cholinergic agonist is a quaternary ammonium muscarinic alkaloid?

Reversible carbamates and irreversible organophosphates

What are the two major classes of indirect cholinergic agonists?

Physostigmine and neostigmine

Which reversible acetylcholinesterase inhibitors are carbamates?

Edrophonium

Which drug is a non-carbamate reversible AChE inhibitor?

Organophosphates

Which class of AChE inhibitors is generally irreversible?

Tabun, sarin, soman

Which are nerve poisons?

Malathion and parathion

Which organophosphates are primarily agricultural pesticides?

Atropine

What is the prototype antimuscarinic alkaloid?

Racemic form

Atropine is what form of hyoscyamine?

CNS penetration decreases

What happens when atropine analogs are converted to quaternary ammonium compounds?

Ipratropium

Which antimuscarinic has a quaternary nitrogen and is used as a bronchodilator?

Dicyclomine

Which synthetic anticholinergic contains a tertiary nitrogen?

Pirenzepine

Which muscarinic antagonist is M1 selective and used for peptic ulcer disease?

Bulky rigid aromatic/cyclic structure

What structural feature characterizes non-depolarizing neuromuscular blockers?

Slender aliphatic molecules with two quaternary nitrogens

What structural feature characterizes depolarizing neuromuscular blockers?

Tubocurarine

Which drug is the prototype non-depolarizing blocker with two cationic heads?

14 Å

Approximately what distance separates the two cationic centers in tubocurarine?

Decamethonium

Which drug is a depolarizing neuromuscular blocker with two quaternary nitrogens and 10 carbons?

Succinylcholine

Which depolarizing blocker contains ester linkages and has a short duration?

Pancuronium

Which steroidal neuromuscular blocker is listed in the module?

Cholinesterase reactivator

What is pralidoxime?

Oxime

What structural group characterizes pralidoxime?

Organophosphates

Pralidoxime is used primarily for poisoning by what class?

Benzene fused to diazepine ring

What is the basic ring system of benzodiazepines?

Positions 1 and 4

Where are the two nitrogen atoms located in the benzodiazepine ring?

3-OH

Which benzodiazepine structural feature is associated with short action?

They undergo glucuronidation

Why do benzodiazepines with a 3-OH tend to be short acting?

They undergo phase I metabolism and may form desmethyldiazepam

What happens to benzodiazepines lacking a 3-OH?

Electron-withdrawing group

Which substituent at position 7 is required for optimal benzodiazepine activity?

Cl and F

Which groups at position 7 increase benzodiazepine activity?

6, 8, 9

Which benzodiazepine positions should generally remain unsubstituted?

Phenyl

What group at position 5 promotes benzodiazepine activity?

Ortho electron-withdrawing substitution

What substitution pattern on the 5-phenyl ring increases benzodiazepine activity?

Activity decreases greatly

What happens with para substitution on the 5-phenyl ring?

Carbonyl

What is optimal at benzodiazepine position 2?

Small substituent

What type of N-substituent is favored in benzodiazepines?

Diazepam

Which benzodiazepine is the most popular prototype in the module?

Oxazepam and lorazepam

Which benzodiazepines listed have a 3-OH?

Barbituric acid

What is the parent compound of barbiturates?