I have just started reading up on structure-based methods for drug design (this is completely not my field so apologies for stupid questions that will be coming along!)

Clearly, some drugs are designed to target the central nervous system. However, I understand that the extracellular fluid of the central nervous system is separated from the blood by the "blood-brain barrier" which restricts the passage of large molecules between the two systems.

My question is : how do you design a drug to be delivered to the CNS?

  • 3
    $\begingroup$ You can read up on the design of opioid drugs (morphine, codeine, etc...). These provide a classic example of rational drug design in relation to the blood brain barrier. $\endgroup$
    – jp89
    Commented Jan 24, 2012 at 23:32
  • 1
    $\begingroup$ I concur with @jp89. Contrast for instance the effects on the human body of pethidine and loperamide. They are structurally similar, yet only the former is able to execute systemic effects. $\endgroup$
    – user132
    Commented Jan 25, 2012 at 1:35

1 Answer 1


In a nutshell: in order to pass through the blood-brain barrier (BBB) the substance has to mimick soee properties of the substances that are allowed to pass through.

There are different types of "transporters" -- integral proteins going through the cell membranes and accounting for the active transport of the substances they can actively bind to. Smaller molecules of drugs can use solute carrier transporter (SLC), whereas bigger molecules (oligo- and polymeres) would use the receptor-mediated transporter (RMT).

There is a nice article on this topic published by ScienceDaily.

Here is the quote:

One technology for enabling active transport of small molecule drugs across the BBB involves targeting endogenous nutrient transporters. These transporters are members of the solute carrier (SLC) transporter superfamily. Transport of small molecules across the BBB by these membrane proteins is known as carrier-mediated transport (CMT).

In order to design drugs that utilize CMT to cross the BBB, researchers modify their chemical structures so that they resemble nutrients that are transported across the BBB by specific SLCs. The prototypical drug that uses this strategy (which was developed long before mechanisms of CMT were known) is L-DOPA, the major current drug for Parkinson's disease. L-DOPA is used to replace dopamine that is lost due to degeneration of dopaminergic neurons in the substantia nigra of the brain.

Another major system that is used in normal mammalian physiology to enable needed molecules to cross the BBB is receptor-mediated transport (RMT). The brain uses RMT to transport proteins, peptides, and lipoproteins that are needed for brain function across the BBB. Examples of biomolecules that are transported into the brain via RMT include insulin, insulin-like growth factor (IGF), leptin, transferrin, and low-density lipoprotein (LDL).

In RMT, molecules in the circulation may bind to specific receptors on the luminal surface of brain capillaries (i.e., the surface that interfaces with the bloodstream). Upon binding, the receptor-ligand complex is internalized into the endothelial cell by a process called receptor-mediated endocytosis. The ligand may then be transported across the abluminal membrane of the endothelial cell (i.e., the membrane that interfaces with brain tissue) into the brain. This whole process is called receptor-mediated transcytosis.


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