Stimulant/Drugs of Abuse Medchem

Question 1

Answer 1

Caffeine
Metabolized by 1A2 (induced by smoking) to 1,7-dimethylxanthine (paraxanthine) which is then further metabolized 1-methyl uric acid

*beware of 1A2 polymorphisms*

Question 2

Answer 2

Theophyline (1,3-dimethylxanthine)

Bronchodilator to treat asthma | weaker CNS stimulant than caffeine

1A2 metabolism to 1- or 3-methylxanthine OR to 1,3-dimethyluric acid

Question 3

Answer 3

S-(+)-amphetamine | Dextroamphetamine

alpha-methyl blocks MAO metabolism

Orally active | greater CNS effects than R enantiomer

Question 4

Answer 4

R-(-)-amphetamine

p450 metabolism (S too) to phenylacetone (inactive)

Question 5

Answer 5

Lisdexamphetamine

Prodrug of dextroamphetamine | ADHD treatment

Question 6

Answer 6

Fenethylline

Prodrug of amphetamine and theophylline

Schedule 1 in US

Question 7

Answer 7

Phentermine

Adds a second alpha methyl (decreases rate of metabolism further)

Reduced stimulant properties compared with amphetamine (less habit forming) | used to manage obesity

Question 8

Answer 8

Methamphetamine

N-substitution/methylation | S-isomer (greater stimulant properties)

Methylation makes it more lipophilic (greater CNS access), more abuse potential

R-enantiomer is Levmetamphetamine (formerly in vicks vapor rub)

Question 9

Answer 9

Diethylpropion

N,N-dimethyl group | structurally similar to bupropion

Decrease stimulant properties | decreased abuse potential

Used to manage weight loss

Question 10

Answer 10

Mescaline | active principle of peyote cactus

Alkoxy aromatic ring substituents

Psychotomimetic and hallucinogenic effects (5HT effects)

Poor oral activity due to rapid MAO metabolism

Question 11

Answer 11

3,4-Methylenedioxymethamphetamine (MDMA) | Ectasy or Molly

N-methyl | alpha-methyl | catechol is capped

Good oral activity, Good CNS actiivty

Metabolism: 2D6/1A2 cap removal, then COMT to HMMA OR oxidation to orthoquinone metabolite (possibly contributes to neurotoxicity through reaction with nucleophiles)

MDMA is a mechanism-based 2D6 inhibitor like paroxetine

Question 12

Answer 12

Methylphenidate

T1/2 = 2-3 hours

Pheynylethylamine gruop | used as R,R and S,S racemate

Dexmethylphenidate is active enantopmer (R,R) - also called Focalin

Esterase metabolism to Ritalinic acid (inactive)

Question 13

Answer 13

Atomoxetine

Structurally similar to fluoxetine and duloxetine | No EWG groups on rings

Selective NE reuptake inhibitor

Non-stimulant used to treat ADHD

T1/2(EM) = 5 hours, 20 in PMs

2D6 metabolism to 4,hydroxyatomoxetine (major, active, T1/2 = 6-8 hours) | metabolites then glucuronidated

DOES NOT INHIBIT 2D6 unlike fluoxetine

Question 14

Answer 14

Modafinil

Stereocenter | Lacks basic amine (will not be charged at physiological pH)

Promotes wakefullness (MOA unclear)

Metabolism: Hydrolysis of amide, oxidation to the sulfone (both inactive)

Armodafani (R-enantiomer) | Both enantiomers active, R has longer T1/2 (3X) at 15 hours

Both enantomers moderately inhibit 2C19 and mdoerately induce 3A4

Question 15

Answer 15

Delta-9 Tetrahydrocannabinol, THC | Dronabinol

Synthetic form of natural constituent from Cannabis plant

Highly lipophilic

Question 16

Answer 16

Nabilone

Avoids allylic oxidation unlike THC

More potent than THC and slightly longer duration

2 methyls block benzylic oxidation

Question 17

Answer 17

Cannabidiol

IND filed for potential treatment of Dravet syndrome, a rare and severe form of pediatric epilepsy

Lacks ring of THC (completely different conformation)