CNS - crossing BBB Flashcards
what is the blood-brain?
Tight Junctions
Absence of fenestrations
Active transport mechanisms (influx and efflux)
Drug metabolising enzymes in brain endothelial cells
What is the blood brain barrier?
A biological barrier at the blood to brain interface, effectively separating the brain from the rest of the body
There are actually 3 barriers
blood-brain barrier (BBB), blood-CSF barrier (BCB), the arachnoid barrier.
Passive diffusion
Passive = Energy not required
Lipid-soluble molecules (logD)
Low polar surface area
Low molecular weight
Small molecules do not necessarily cross the BBB (98% of all small molecules do not cross, only 5% of the >7000 drugs in CMC database treat the CNS)
active efflux (and influx)
active - ATP req
xenobiotics, metabolites, toxins, drugs
many transport from endothelium to blood
some bi-directional
carrier-mediated transport
essential polar molecules
glocose, a.a
CMTs - encoded genes within soliute carrier transporter gene family
preferential distribution across both sides of BBB confers polarised behaviour of BBB
transcytosis (RMT & AMT)
RMT (receptor-mediated transcytosis)
- molcules too large to use CMT (peptide bonds)
- regulatory proteisn, hormones, growth factors
specific receptors on cell surface are responsible
AMT (adsorptive-mediated transcytosis)
+ively charged, large mols
histone, protamine,m cationic, proteins
cell surface binding sites (+ive proteuns, -ive cell surface electrostatic interactions
Cell Diapedesis
Most common example is Neutrophils (WBC) that provide defense against invading microorganisms and so must be able to cross the endothelial BBB.
used for tissue repair but if not controlled can lead to inflammation (e.g. arthritis, vascular inflammation etc)
Can be manipulated to transport drugs across the BBB
Chemical modifications for drugs to cross BBB
LIPINSKI’S RULE OF 5 – MEMORISE
1) 5 or fewer Hydrogen Bond Donors (HBD)
2) 10 or fewer Hydrogen Bond Acceptors (HBA)
3) Molecular weight under 500 g/mol
4) LogP less than 5 (Actually: 0-3 for CNS)
5) 10 or fewer rotatable bonds
Polar surface area
taken upo by polar atoms
TPSA - topological polar surface area
measured ion squared angstroms
oral bioavail. <140 A
to cross inton CNS <90 A
what are the ideal charicteristics for cns drugs
HBD: 5 or fewer
HBA: 10 or fewer
MW: 450 g/mol or less
RB: 10 or fewer
LogD: 0-3
PSA: <90 Å2
Chemical Methods
Lipophilic Analogues
Prodrugs
Chemical Delivery Systems
Molecular Packaging
LIPOPHILIC ANALOGUES
Lipid solubility is a key factor in passive diffusion across BBB
Making drug molecules more lipophilic is logical
Involves adding lipid groups to polar ends of drug molecules
Can lead to poor tissue distribution
Can be detrimental to oxidative metabolism by CYP-450 and other enzymes
Also lowers PSA so can change bioavailability (especially oral drugs)
Prodrugs
must undergo chemical conversion by metabolic process before becoming an active phrenological=al agent
- used to make the drug more lipophilic
- some prodrugs alter original tissue distribution, efficacy and toxicity of parent drug
Chemical delivery systems (CDS)
Inactive chemical derivatives of a drug obtained by one or more chemical modifications.
Provide site-specific or site-enhanced delivery of the drug through multistep transformations
There are three main classes of CDSEnzymatic
- Enzymatic Physiochemical CDS
2.Site-specific Enzyme-activated CDS
3.Receptor-based CDS
Two types of bioremovable moieties are introduced to convert the drug into inactive precursor:
Targetor: Responsible for targeting, site-specificity and lock-in
Modifier: Lipophilizers, protect certain functions, prevent unwanted or premature metabolic conversions
Sequential metabolic conversions disengage the modifier and then the target once they have completed their roles
Primarily used for peptides
The peptide unit forms part of a bulky molecule, dominated by groups that prevent recognition by peptidases and allow for direct passage through BBB
achieve 3 goals simultaneously:
Increased lipophilicity (enhance passive transport)
Prevention of premature degradation (by enzymes especially)
Exploits lock-in mechanism to make targeting possible
