CNS drugs, clinical trials and BBB

what are CNS drugs used for

they act on CNS to alter mood, behaviour, perception or consciousness

what are the main categories of CNS drugs

• depressants

• stimulants

• analgesics

• antipsychotics

• antidepressents

• anxiolytics

why are CNS disorders increasing

due to aging population and increased life expectancy

examples of CNS disorders associated with aging

• Alzheimer’s disease

• Parkinson’s disease

• stroke

• depression

• epilepsy

why is drug delivery to brain difficult

due to blood brain barrier which restricts entry of most drugs via oral or IV injection

100% of all proteins and nucleic acids and 98% of small molecules cannot enter CNS

what structures contribute to CNS drug delivery barriers

• BBB

• cerebrospinal fluid (CSF)

• systemic dilution of drugs in circulation

the CNS is extremely sensitive - what is BB designed to do

• protect against toxins

• maintain stable environment

• strictly control what enters the brain

why is the BBB so selective

• tight junctions prevent paracellular diffusion

• only selective transport or passive diffusion allowed

how do most drugs cross BBB and what are the features that the drug must have

passive diffusion across cell membranes

therefore drug must be:

• small

• lipophilic

• non-polar

why is high blood concentration important for CNS drugs

because brain and blood concentrations reach equilibrium → enough drug must be in blood to reach receptors

what are the strategies to improve CNS drug delivery

• intracranial delivery

• BBB disruption (temporary)

• modify P-glycoprotein transport

• intranasal delivery

• nanotechnology

what structural feature makes the BBB so restrictive

tight junctions between endothelial cells

• prevent paracellular (between-cell) diffusion

• force substances to go through cells, not between them

how is BBB permeability different from intestinal permeability

there is poor correlation between Caco-2 (intestinal) permeability and BBB transport

how does drug solubility affect BBB penetration

drug solubility depends on:

• molecular structure

• distribution of polar vs non-polar regions

• intermolecular forces in solid form

how does systemic distribution affect CNS drug delivery

drugs are diluted throughout the body - only a fraction reaches the brain

what happens if the BBB is disrupted

because it can be neurotoxic and damage brain protection systems

Lipinski’s rule of five: what are the parameters for poor absorption/permeation of the drug

poor absorption/permeation if compound has:

• more than 5H-bond donors (sum of OHs and NHs)

• more than 10H-bond acceptors (sum of Ns and Os)

• MW>500

• LogP>5

Lipinski’s rule of five: what are the parameters for CNS penetration of drug

CNS penetration likely if:

• MW<400

• LogP<5 or equal to

• H-bond donors <3 or equal to

• H-bond acceptors <7 or equal to

summary of a successful CNS drug parameters

• potent activity is low

• highly selective

• MW < 450

• minimal hydrophobicity (clogP < 2.5)

• H-bond donors < 3

• H-bond acceptors < 8

• pKa 7.5-10.5 (avoid acids, keep neutral or basic)

• H-bonds < 8

• plus all the ones of the slide

why are CNS clinical trails difficult compared to other areas

because:

• CNS diseases involve complex brain functions

• outcomes are hard to measure objectively

• many drugs fail to show clear improvement over existing therapies

the first major challenge in CNS clinical trails: achieving measurable improvement in cognitive function - why?

• aim is to improve cognition by counteracting brain damage caused by disease

• but this depends heavily on disease stage

why is disease stage critical in CNS trails

• mild cognitive impairment → improvement possible

• severe neurodegeneration → structural brain damage too advanced

why are early-stage patients considered ‘good experimental subjects’

• brain structure less damaged

• cognitive decline is still reversible or modifiable

so drug effects easier to detect

why are elderly patients with advanced disease ‘poor-experimental subjects’

• often have multiple conditions (e.g. dementia and depression)

• cognitive performance varies significantly

• improvements may be indirect (e.g. mood, motivation) rather than true cognitive change

what is the second major challenge in CNS trials

interpreting whether observed changes are truly due to drug

why must CNS trials be conducted in ‘neutral environment’

to eliminate external factors that affect cognition like mood, motivation, arousal levels

how can side effects interfere with trials

improvements in cognition may actually be due to:

• increased alertness

• reduced anxiety

• improved mood

why do many CNS drugs fail in clinical trials

• Difficulty achieving measurable endpoints

• Poor trial design

• Inappropriate patient selection

• Indirect or confounded effects

• many compounds fail to show significant benefit over current therapy