Review: Optimizing CNS access

Neurotherapeutic agents generally illicit their effects by acting on receptors in the central nervous system (CNS) and a short review in Expert Opin. Drug Discov. highlights the current best practices and recent developments in targeting molecules to the brain.  The key areas covered in this concise overview are:

  • Design strategies for optimizing unbound brain concentration in the CNS.  Recent publications (e.g. Wager, Desirable Central Nervous System Drug Space…;  and the earlier Hitchcock,, Structure−Brain Exposure Relationships) have highlighted the key physicochemical property space within which CNS drugs are located and to which drug discovery efforts ought to ostensibly be aligned in order to achieve the required balance of efficacy and safety. However, the authors stress that optimizing unbound brain and plasma concentration ratios (or brain availability) by adopting a more holistic, multi-parameter approach is crucial to success (and they refer back to another of their own recent publications in this vein).  Structural elements associated with blood-brain barrier (BBB) penetration and computational approaches to predicting BBB permeability are also discussed briefly.

Physicochemical property space - CNS drugs and candidates (click to enlarge)

  • Screening strategies to optimise brain availability.  This section looks at the role of transporters (e.g. P-gp) in controlling molecular access to the CNS and at in-vitro and in-vivo screening approaches to addressing this issue in drug discovery.  The recent publication of the mouse P-gp x-ray crystal structure (PDB3G60) and it’s implications are also discussed.
  • Brain Delivery Approaches. Molecules with properties that fall outside the property space of known CNS drugs (e.g. antibodies, siRNA, peptides) offer novel approaches to the treatment of CNS disease and numerous innovative approaches to the delivery of such agents are under investigation.  The final section summarizes progress in this area.
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