MedChem

What is the pharmacophore in antipsychotics? 

Chlorpromazine

What is important about chlorpromazine?

• pharmacophore: phenothiazine

• EWG Cl @C2 

  • enhances binding and penetration into CNS 

• 3C spacer to tertiary amine

  • responsible for pharm activity 

  • metabolites are not active, or very weak 

• dialkylamines 

Triflurpromazine

What is important about triflupromazine? 

• pharmacophore: phenothiazine

• trifluoromethyl @C2

  • more lipophilic → enhances binding affinity and increases EPS

  • superior potency versus chlorpromazine

Methotrimeprazine

What is important about methotrimeprazine? 

• pharmacophore: phenothiazine

• EDG @C2

  • less lipophilic → lower CNS side effects

  • polar substituent → decreased half-life and potency

• methyl group of 3C spacer

  • R-enantiomer active (also analgesic)

Pipotiazine

What is important about pipotiazine?

• pharmacophore: phenothiazine

• polar dimethylsulfonamide @C2

  • decreases CNS penetration, EPS and half-life 

  • sulfonamide, has risk of allergy 

• cyclic amine (piperidine) + alcohol group

  • more polar 

  • better binding affinity to D2 receptor 

Perphenazine

What is important about perphenazine? 

• pharmacophore: phenothiazine

• EWG chlorine @ C2

• piperazine + alcohol after 3C spacer 

  • more lipophilic so less CNS side effects

  • enhances binding affinity to D2 

Fluphenazine

What is important about fluphenazine?

• pharmacophore: phenothiazine

• EWG trifluoromethyl @ C2

  • superior potency

• piperazine + alcohol after 3C spacer 

  • more lipophilic so less CNS side effects

  • enhances binding affinity to D2 

What are the in vivo metabolites of chlorpromazine?

• 3A4/1A2

  • sulfone 

  • NO activity

  • associated with CV toxicity

• 2D6

  • oxidation of benzene to hydroxy 

  • some activity 

• 1A2 

  • secondary amine 

  • inactive 

What is the bioactive conformation of phenothiazines?

• cis-conformation of phenothiazines have similar geometry as trans-dopamine (active conformation)  

  • will act as competitive blocker and prevent DA from biding 

• EWG @ C2 will promote bioactive conformation

  • protonated amine can interact with EWG and cation pi interaction lock in Cis conformation 

What is the SAR of phenothiazines?

• ring A 

  • EWG @C2/3 increase D2 receptor binding 

  • polar @C2/3 decrease CNS effects 

  • C1/4 substitution decrease activity 

• ring B - @N10 

  • need 3C spacer; anything else decreased activity 

  • tertiary amine better activity 

  • piperazine > piperidine > aliphatic amine 

  • hydroxypiperazines > alkyl piperidine 

• ring C

  • unsubstituted at all positions 

Thiothixene

What is important about thiothixene? 

• pharmacophore: thioxanthene

  • lower binding affinity vs phenothiazines

• @C10 - double bonded to first C in Z-isomer better activity 

  • piperazine

• sulfonylamide @C2

  • more polar, decreases half-life and EPS

Zuclopenthixol

What is important zuclopenthixol?

• pharmacophore: thioxanthene

• EWG Cl @C2

• @C10 - double bonded to first C in Z-isomer better activity 

  • piperazine + hydroxy → better binding 

• can be converted to a prodrug ester 

What is the bioactive conformation of thioxanthines?

• Z-isomer overlaps with trans-dopamine conformation 

  • piperazine and halogen on the same side 

Clozapine

What is important about clozapine? 

• pharmacophore: dibenzodiazepines 

  • faster dissociation (less tight binding) 

• piperazine w/ tertiary amine 

  • enhances binding affinity

  • secondary weak activity 

• EWG Cl @C2 → enhances binding affinity 

• central ring 

  • can have positive charge and oxidized species → leading to agranulocytosis 

Olanzapine

What is important about olanzapine?

• pharmacophore: dibenzodiazepine

• similar structure to clozapine → 1 benzene change to thiophene

  • risk of oxidation of central ring lower → reduced risk of agranulocytosis 

  • enhanced bioavailability and half-life 

Quetiapine

What is important about quetiapine?

• pharmacophore: dibenzothiazepine

• similar structure to clozapine

  • addition of ester → polar agent, conjugation (phase II) reaction can occur so faster elimination (shorter half-life) 

  • change sulphur vs N in central ring → can undergo oxidation to sulphone or sulfoxide which is not active 

Haloperidol

What is important about haloperidol?

• pharmacophore: butyrophenone

• 4 carbons +benzene + ketone 

• piperidone + hydroxyl → needed to bind 

  • hydroxyl can be converted to ester prodrug 

• chlorobenzene → lipophilic and enhances penetration into brain 

• better binding to D2 and slow dissociation 

What is the risk of one of haloperidol’s metabolites? 

• Can produce an aromatic leading to a positive charge on the N of piperidine ring via dehydration + oxidation 

  • positive charge can is a toxic metabolite of DA producing cells in brain 

  • = neurotoxic 

Risperidone

What is important about risperidone? 

• derivative: butyrophenone-like

• isoxazole

  • enhances binding to 5-HT 

  • increases oral bioavailability and half-life 

• C9 can undergo oxidation to hydroxy → equal activity 

  • is paliperidone 

Ziprasidone

What is important about ziprasidone? 

• derivative: butyrophenone-like

• thiazole

  • enhances binding

  • can undergo oxidation → lower bioavailability and half-life  

Aripiprazole

What is important about aripiprazole?

• butyrophenone-like derivative 

• quinolinone → enhances binding 

  • convert to 1 double bond → more active and longer half-life (48-68h) 

• dichlorobenzene 

  • enhances binding affinity 

  • better bioavailability and half-life

  • more lipophilic and more into brain 

Pimozide

What is important about pimozide?

• diphenylbutylpiperidine derivative

• diphenol w/ fluorine

  • lipophilic → enhances half-life (55h)

  • binds to cholinergic receptors

• imidazole for activity

• binds to D2 and 5-HT2A