At low doses: 

1. Competitive inhibitor of adenosine receptors (A1 & A2a)
2. Inhibits phosphodiesterases, which increases cAMP and sensitivity to stimuli

At high doses:

1. Stimulates Ca release in SR of skeletal muscles and increases contractile function
2. promotes central release of NE via GABAR

True or False? and why?

Increased consumption of caffeine causes gout.

False

Methylxanthines do not metabolize into uric acid.

True or False? and why?

Caffeine metabolism does not generate theobromine.

True.

During metabolism, caffeine is converted to theophylline and paraxanthing via P450, but it does not convert to theobromine.

Why is chocolate so harmful to puppies?

Chocolate contains the xanthine theobromine amongst other things.

The lethal dose of chocolate in humans is 200mg/kg, whereas in puppies its half of that. Taking also into consideration that puppies are considerably smaller, a 6oz chocolate bar can kill a 7kg puppy.

• anxiousness/nervousness
• muscle twitching
• insomnia
• rambling flow of thought and speech
• tachycardia or cardiac arrhythmia

True or False?

Acute caffeine toxicity can lead to miscarriages.

False

Chronic caffeine toxicity is associated with miscarriages. When taking 200mg/day (1 1/2 cups of coffee) the risk of miscarriage is doubled (greatest risk seen in 8 weeks of pregnancy).

There is no apparent increased risk of birth defects with caffeine use.

Hydroxyl groups on dopamine make it incapable of crossing the blood brain barrier because it is hydrophillic.

Also, the lone amide group makes dopamine very susceptible to MAO metabolism.

Amphetamine

ritalin

phenmetrazine

Methylenedioxyamphetamine

(MDA)

pseudoephedrine

Describe the SAR of amphetamines.

1. Distance between the phenyl and nitrogen is important
2. Stereochemistry: S+ is 4xs greater in activity than R- in the brain, but equipotent in the periphery
3. 1S:2R or 1R:2S is very ephedrine like, whereas 1R:2R or 1S:2S is a nasal decongestant
4. EWDGs or EDGs on the phenyl ring will decrease the activity, but the EDGs will also increase the psychedellic effects
5. Methyl substituion or inclusion of the nitrogen in ring will retain CNS stimulatory activity, increases distribution across the BBB, and usually increases duration of action

True or False? and why?

The toxic effects of amphetamines are due to its cardiostimulatory effects.

False.

The toxic effects are seen in excess of dopamine neurotransmitters in the synaptic cleft.

1. oxidative damage is done by its production
2. toxic aldehydes form from its MAO metabolism

What is the effect of amphetamines at low doses?

Release of biogenic amines (primarily NE) and inhibits its reuptake.

+Effects

• Enhanced physical performance
• increased alertness
• little need for sleep

-Effects

• None

Straterra

Atomoxetine

1. Norephedrine
2. p-Hydroxynorephedrine
3. Hippuric acid

• Dopamine beta-hydroxylase
• MAO
• P450 Hydroxylation

Illegally:

• Sudafed
• Iodine
• Hydroioidic acid (HI)
• Red phosphorous (match books)

Industrially:

• NaBH4
• phenylacetone
• methylamine (CH3NH2)

Describe the SAR of cocaine.

1. Must have cis-chair configuration in order to be active
2. C-2 substituent is best with smaller ester
3. C-2 stereochemistry is 200 fold more active in the beta form vs. the alpha form.
4. C-3 substituent can have positive/negative activity effects

cocaine

Benzyolecgonine

Ecgonine

Norcocaine

P450 - demethylation

Esterases

Discuss the differences and similarities between cocaine and cocaethylene.

Differences:

• Cocaine > cocaethylene in binding to 5HT transporter
• Cocaethylene > cocaine euphorogenic

Similarities:

• Equipotent DA transporter affinity

Acidic cocaine is more soluble in water but is less distributed across the BBB.

Although it has poor solubility, free base cocaine has great passage across the BBB and when smoked, its distribution may be similar to IV injection.

cocaethylene

Describe the SAR for psychedellic phenethylamines like MDA.

1. Ethylamine group is responsible for stimulatory effects

2. Methoxy/alkoxy substituents on phenyl ring is responsible for psychedelic properties

mescaline

What are the enzymes that act on pyschedellic phenethylamines and where do they act?

MAO - deamination of amine

P450 - attacks methylene (on ring)

DBH - hydroxylation of ethyl group

fluoxetine

True or False? and why?

MDMA and concominant fluoxetine use is contraindicated.

True

Fluoxetine is a potent P450 inhibitor. Concominant use with MDMA will increase the bioavailability of MDMA through delayed clearance.

True or False? and why?

MDMA use should be avoided when currently on MAOI therapy.

True

MDMA is a pootent MAOI. Concominant therapy may exacerbate effects. Such MAOIs to avoid are: phenelzine, tranylcypromine, isocarboxazid.

CB1 = cannaboid receptor 1 

Similarities:

• Both bind to CB1/CB2 receptors
• Binds to CB2 receptors with equipotency

Differences:

• 2-AG>AnNH in CB1 affinity

Euphoria

Nausea suppression

Releif of anxiety

Stimulation of appetite

Pain releif

Decrease occular pressure in glaucoma patients

Extended periods of high exertions leading to:

• dehydration
• electrolyte imbalance
• high body temperature (hyperthermia, heat stroke)

LSD

DMT

psilocin

psilocybin

True or False? and why?

Without CB1 receptors, one can not condition oneself.

False.

Studies have shown that the lack of of CB1 receptors has shown defective deconditioning behavior.