CNS acting drugs

antipsychotics MOA

• generally involes modulation/blockade/decrease of limbic (emotional nervous system) dopamine (DA) neurotransmission

• mostly Ix w/ dopamine D2 receptors but also display affinity for other neuroreceptors

  • triggering bioactivity at other receptors can lead to SE’s, but also can be responsible for the drug’s efficacy

structure of antipsychotics

• are lipophilic dopamine mimetics (look alikes)

  • high drug logP/lipophilicity accounts for significant CNS/brain penetration and accumulation

what are the 3 key chemical features of antipsychotics, and what are their roles?

• aromatic unit (lipophilic)

  • increases drug lipophilicity + permeability thru membrances, esp the BBB to act and accumulate in the CNS

  • single/multi ring system, often w halogen groups to boost lipophilicity

• amino unit (basic)

  • ionisable alkyl or heterocyclic 3* amine group

  • can be reacted w strong acids to form water sol. salts → to deliver drug in aq dosage form

• aliphatic linker unit

  • small fatty unit, often alkyl (carbon) based

first gen antipsychotics

• function as potent dopamine D2 antags

• but display lack of receptor specificity → can lead to undesireable SE’s

phenothaizines v.s. thioxanthenes

• phenothiazines → extra N in aromatic ring structure

• thioxanthenes → double bond in linker chain unit

phenothiazines + thioxanthenes tricyclic ring substitution

• only v minimal ring substitution on ring C is permitted → <2 ring subs diminishes bioactivity

  • vast majority of drugs only possess one ring C sub

• 2-C sub → shld be EWG for optimal dopamine (DA) binding

phenothiazines + thioxanthenes terminal amino unit

• piperazine based drugs possess the highest affinity for dopamine receptors and are the most potent antipsychotics

  • piperazine > piperidines > alkylamines

• piperazine based drugs also possess the lowest affinities for other receptors (ACh, H1 and a-1) → hence less likely to induce sedation + orthostatic hypotension

• piperidine based drugs have lowest incidence of EPSE due to their dual DA and ACh receptor activities

clinically available phenothiazine + thioxanthene antipsychotic drugs

• left → alkyl amine

• middle → piperidine based drug

• right → piperazine based drug (2 N)

• chlorpromazine → first antipsychotic

  • when Cl is replaced w CF3 (trifluoromethyl) → drug potency increases due to EWG effect + increased lipophilicity

    • same applies to perphenazine (X = Cl) and fluphenazine (X = CF3)

    • F → highly electronegative → electron withdrawing

    • halogens also increase potency + lipophilicity

• 100mg of chlorpromazine = activity of 25mg triflupromazine

  • triflu more potent as it req a lower dosage in order to induce the same pharmacology

• mesoridazine (drug in the middle) → piperidine unit (1 N) will hv less SE’s assoc.

• piperazines (2N) most potent → v small doses for approx equiv dose

  • piperazines can also terminate w a hydroxy (OH) unit which can be exploited → ester prodrugs can be formed (see next slide)

• thiothixene (bottom) → is a thioxanthene, has a double bond instead of the N in the tricyclic ring

  • 100mg chlorpromazine = 5mg thiothixene

  • thiothixene has a piperazine unit (2N) → v potent

phenothiazine + thioxanthene ester prodrugs

• majority of phenothiazine drugs undergo extensive hepatic metabolism to many inactive + active metabolites → therefore bioavail drops significantly

• use of highly lipophilic ester prodrugs provides 4-10x more oral bioactivity

  • HC rich fatty ester units → forms depot/SR forms

  • IM depot of drug can also improve pt compliance → don’t hv to take meds orally everyday, may be a challenge in some pts

• ester prodrugs can also be generated for drugs with a hydroxyl containing alkyl substituent on the terminal amino unit

  • these func. as long-acting drug forms that undergo slow/sustained bioactivation via plasma esterase hydrolysis

phenothiazine + thioxanthene ester prodrug examples

• COO-R → promoiety unit which over time is hydrolysed to generate the active alc form

• increasing the ester chain length (R) → will increase drug duration/depot effect

butyrophenones + diphenylbutyl piperidines structure

• butyrophenone → keto carbonyl unit (C=O)

• diphenylbutyl piperidine → 2 benzene rings

these drugs tend to be more lipophilic → hence more potent than the tricyclics, esp the diphenylbutyl drugs as they have 2 benzene rings

butyrophenones + diphenylbutyl piperidines aromatic + linker units

• monosub of the phenyl ring(s) with a para 4-fluoro sub (X=F) results in the most potent compounds

  • Cl also works but is not as effective

• diphenylbutyl piperidines → have an additional benzene ring instead of the keto unit on the 4C linker chain

  • hence are more lipophilic → greater potency

piperidine unit of butyrophenones + diphenylbutyl piperidines

• basic and ionisable amino unit is essential for DA receptor binding and activity

• para (4) R1 and R2 positions are most tolerant to substitution

  • sub at pos 2/3/5/6 → decreases neuroleptic activity

clinically available butyrophenone drugs

• butyrophenones + diphenylbutyl piperidines are typically much more potent antipsychotics

• pipamperone

  • OH replaced w 1° amide (CONH) unit

  • and benzene ring replaced w another piperidine unit → becomes a bis-piperidine

• droperidol

  • short acting sedative and post-op antiemetic

  • amide (CONH) is closed off to form a ring part of a 2 ring structure→ spirocarbocyclic agent

clinically available diphenylbutyl piperidines

• diphenylbutyl piperidine drugs → tend to hv greater potency and lipophilicity = increased bioavail + CNS absorption

• pimozide (droperidol) → also has the spirocarbocyclic ring system (CONH ring)

  • 2mg is equiv to 100mg chlorpromazine, v high potency

anxiolytics MOA

• consist of benzodiazepine drugs used for the Tx of anxiety Sx + disorders

• BUT unlike other CNS drugs, anxiolytics are NOT neurotransmitter mimetics → do NOT resemble GABA

  • anxiolytics instead Ix w an extracellular benzodiazepine binding site (BZR) inducing a conformational change in the GABA-a receptor, promoting GABA (gamma-aminobutyric acid) neurotransmitter binding → encourages flow of Cl across the receptor from one side of the cell to the other

  • they do not need to resemble GABA as they operate at a diff site within the receptor

benzodiazepines structure

• 1,4-benzodiazepine-2-one

  • has a 2-ketone on the B ring

• azolo[1,4]benzodiazepine

  • has an additional azole ring D, fused to the B ring

rings A and C in benzos

• both ring A and C are impt for effective binding to the BZR within GABA-a receptor

• ring A system, which is typically a benzene ring, Ix via pi-pi aromatic ring stacking w various AA residues within the BZR site

  • ring A sub at C-7 → usually EWG

    • improves binding to receptor, improves potency of drug

  • ring A sub at C-6/8/9 → no go zones, sig. drop in bioactivity

• BUT ring C isn’t essential → compounds w/o that phenol ring can still operate at GABA-a receptors

  • but the presence of the C ring enhances/improves binding and efficacy of drugs

  • binding occurs thru various hydrophobic Ix

  • ring C sub at C-2/6 → EWG, improves binding and potency of drug

    • usually halogens

    • EDGs instead will diminish potency

  • ring C sub at C-3/4/5 → no go zones

    • drug will not work

ring B on benzos

• ring B is needed for optimal BZR binding → must contain at least 1 proton accepting group for H bonding to histidine residues

• for optimal activity → R1 sub = H, CH3 or small alkyl group

  • v bulky groups are not well tolerated

• R3 sub → small sub is tolerated

  • R3 = OH increases P2 metabolism to give shorter acting agents

diazepam structure

• amide/lactam based drugs

  • -zepam → lactam unit in drug

• R3 = H (i.e. un-subbed)

clinically available diazepams

• tetrazepam + bromazepam → doesn’t hv a benzene ring

  • bro → also weak basicity, and has a Br instead of Cl/F

• clobazam → lactam unit at the top + at the bottom

  • has a tertiary amine unit

• cloxa + haloxa → unusual oxazolidine ring system

• clorazepate → CO2K prodrug to improve aq solubility

oxazepams structure

• related to diazepams, but hv an additional sub in ring B at pos 3

  • R3 = OH

• due to the polar OH unit → less lipophilic drugs, possess a shorter DOA

azolobenzodiazepines structure

• have an additional ring D → azole

• loprazolam → has a fairly large unit extending out from the side of ring D

  • is a piperazine (2N) based unit that ionises fairly readily and can be converted into HCl salt form for aq delivery

antidepressant MOA

• blockade of monoamine neurotransmitter transport/reuptake

  • inhibit the neuronal reuptake of norepinephrine (NE) and/or serotonin (5-HT) into presynaptic neurones from the synaptic cleft → raising neurotransmitter lvls

chem structure of antidepressants

• are lipophilic monoamine mimetics that contain 2 key features:

  • aromatic unit (lipophilic)

  • amino unit (basic) → 1* amine (-NH2)

• like all other CNS acting drugs, possess high lipophilicty for significant CNS penetration/accumulation

tricyclic antidepressants structure

• func. as non-selective norepinephrine (NE) and serotonin (5-HT) reuptake inhibitors (NSRIs) or selective NE reuptake inhibitors (SNRIs)

• have a lipophilic ‘6-7-6’ tricyclic system and must conform to this chemical template

  • tricyclic aromatic ring unit (lipophilic)

  • aliphatic side chain linker unit

    • mostly fatty 3C

  • terminal amino unit (basic)

    • mostly ionisable alkyl 2* or 3* amine

tricyclic ring sub

• tricyclic ring dictates drug potency, but possesss little significance w 5-HT and NE activity

• ring sub is uncommon but may improve 5-HT affinity selectivity

3* amine TCA’s

• NSRIs

2* amine TCA’s

• SNRIs