MEDCHEM - ZHANG -STIMULANTS

Topics to cover/stimulants covered

Stimulants

• Caffeine

• Amphetamine and analogs

• Cocaine

Caffeine Points

• caffeine occurs naturally in a number of plant producsts

• possesses mild central stimulant activities (reduces fatigue, restores alertness) and metabolic stimulant activities (weight loss products)

• Beverages

  • Coffee

  • Tea

  • Chocolate

  • Guarana

  • Kola

What makes up amphetamines?

CCNS stimulants

Phenylalkylamines

• Phenylisopropylamines

• Methamphetamine/Amphetamine

What are the steps of AMPHETAMINE metabolism

1. N-hydroxylation

   1. Conjugations are excreted

   2. NH becomes double bond - turns into Oxime

2. Oxime undergoes dehydroxylation into P2P

3. P2P is carboxylated ( takes away [O]) into benzoic acid

SAR and stereochemistry of Amphetamines

S(+) isomer is more potent than the R(-) isomer

S(+) isomer = Dextroamphetamine

R isomer = Levamphetamine

Adderall to treat ADHD is a mixture of equal amount of 4 salts

1. Amphetamine aspartate

2. amphetamine sulfate

3. amphetamine saccharide

4. amphetamine sulfate

If you remove the methyl from the amphetamine molecule, you get____

A molecule with LESS lipophilicity and more metabolism

If you add an extra methyl to the amphetamine molecule, you get____

A molecule with REDUCED STIMULANT activity but more stable to metabolism

SAR for the terminal amine on amphetamine

N-methyl > primary > tertiary is terms of potency

• think (N-methyl is methamphetamine)

What other molecule/drug is created by adding a L-Lysinly to the terminal amine on the Amphetamine molecule?

Vyvanse!!!!
- it is a prodrug

SAR of amphetamine at the beta position (ephedrine - addition of an OH)

• Introducing a B-OH group leads to reduced stimulant potency

• Ephedrine vs norephedrine

• Two chiral centers - 4 isomers

• RR and SS isomers are pseudoephedrine and pseudonorephedrine

SAR of amphetamine at the beta position (cathinone - addition of an ketone group)

• cathinone is equal potent as stimulant compared to amphetamine

• A natural product from that (illegal in the US)

• Schedule 1 substance

• SAR of amphetamine is applicable

• cathinone vs methcathinone

Ephedrine can be created into ______ and ______

• Methamphetamine (by dehydroxylation of beta)

• Methcathinone (by hydroxylating the OH into a C=O)

Phenylalkylamines MOA

• Methylphenidate and Dexmethylphenidate

• Both act in a manner similar to cocaine by blocking DA reuptake through interacting with DAT to increase synaptic concentration of DA

Points about Serdexmethylphenidate

• Prodrug of dexmethylyphenidate

• Approved for ADHD treatment by the FDA in March 2021

Points about other molecules than Phenylalkyl amines

• modafinil (provigil); mild stimulant for ADHD

• Low abuse potential

• Two optical isomers

• Modafinil is a racemic mixture

• R isomer — longer half life than modafinil — may be more effective at improving wakefulness in patients with daytime sleepiness

Points about Viloxazine (Qelbree) and Centanafadine (SImtriyo)

Viloxazine (Qelbree)

• SNRI for ADHD

Centanafadine (Simtriyo)

• First and only approved NE, dopamine, SRI (NDSRI) for treatment of ADHD