CNS - crossing BBB

Question 1

what is the blood-brain?

Answer 1

Tight Junctions
Absence of fenestrations
Active transport mechanisms (influx and efflux)
Drug metabolising enzymes in brain endothelial cells

Question 2

What is the blood brain barrier?

Answer 2

A biological barrier at the blood to brain interface, effectively separating the brain from the rest of the body

Question 3

There are actually 3 barriers

Answer 3

blood-brain barrier (BBB), blood-CSF barrier (BCB), the arachnoid barrier.

Question 4

Passive diffusion

Answer 4

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)

Question 5

active efflux (and influx)

Answer 5

active - ATP req
xenobiotics, metabolites, toxins, drugs
many transport from endothelium to blood

some bi-directional

Question 6

carrier-mediated transport

Answer 6

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

Question 7

transcytosis (RMT & AMT)

Answer 7

RMT (receptor-mediated transcytosis)

• molcules too large to use CMT (peptide bonds)
• regulatory proteisn, hormones, growth factors

specific receptors on cell surface are responsible

Question 8

AMT (adsorptive-mediated transcytosis)

Answer 8

+ively charged, large mols

histone, protamine,m cationic, proteins

cell surface binding sites (+ive proteuns, -ive cell surface electrostatic interactions

Question 9

Cell Diapedesis

Answer 9

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

Question 10

Chemical modifications for drugs to cross BBB

Answer 10

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

Question 11

Polar surface area

Answer 11

taken upo by polar atoms
TPSA - topological polar surface area

measured ion squared angstroms

oral bioavail. <140 A

to cross inton CNS <90 A

Question 12

what are the ideal charicteristics for cns drugs

Answer 12

HBD: 5 or fewer
HBA: 10 or fewer
MW: 450 g/mol or less
RB: 10 or fewer
LogD: 0-3
PSA: <90 Å2

Question 13

Chemical Methods

Answer 13

Lipophilic Analogues
Prodrugs
Chemical Delivery Systems
Molecular Packaging

Question 14

LIPOPHILIC ANALOGUES

Answer 14

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)

Question 15

Prodrugs

Answer 15

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

Question 16

Chemical delivery systems (CDS)

Answer 16

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

Question 17

There are three main classes of CDSEnzymatic

Answer 17

1. Enzymatic Physiochemical CDS
   2.Site-specific Enzyme-activated CDS
   3.Receptor-based CDS

Question 18

Two types of bioremovable moieties are introduced to convert the drug into inactive precursor:

Answer 18

Targetor: Responsible for targeting, site-specificity and lock-in
Modifier: Lipophilizers, protect certain functions, prevent unwanted or premature metabolic conversions

Question 19

Sequential metabolic conversions disengage the modifier and then the target once they have completed their roles

Answer 19

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

Question 20

achieve 3 goals simultaneously:

Answer 20

Increased lipophilicity (enhance passive transport)

Prevention of premature degradation (by enzymes especially)

Exploits lock-in mechanism to make targeting possible