There are over 200 FDA-approved CNS drugs. It may take a while, but we plan to catalog and describe them as best we can in terms of medicinal chemistry features and any interesting drug discovery aspects we find and can learn from.

Alphabetically speaking, it will begin with Acamprosate, and after a quick look at its sulfonic acid structure, one might not think it even capable of crossing the blood-brain-barrier at all.  It’s pKa is less than -1, and the sweet spot for brain penetration is a pKa of between 4 and 10.  A strong acid (e.g., pKa <4), or a strong base for that matter (pKa >10), will be fully ionized at physiological pH, and these compounds rarely penetrate the BBB (to a significant extent).

​Guidelines limiting the pKa of a compound to between 4 and 10 for a CNS compound have been suggested; see Fischer, H., Gottschlich, R., Seelig, A. (1998). Blood-brain barrier permeation: molecular parameters governing passive diffusion. J. Membrane Biol. 165, 201–211.

​Furthermore, the lipophilicity of Acamprosate (cLogP = -1.1) is out of line with that considered optimal for CNS penetration.

A large number of different guidelines for predicting BBB permeation based on structural properties have now been proposed, which generally suggests preferred ranges for LogP of between 1 and 5.

These guidelines refer to passive permeability. Acamprosate may be actively transported across the blood-brain-barrier (we need to look into this). Taurine itself is actively transported into the brain and has a very similar structure to Acamprosate. In addition, Acamprosate is administered clinically at relatively high doses (e.g., 333 mg orally) so perhaps “enough” does get to the active sites.

Based on the free-drug hypothesis, brain penetration is expressed in terms of unbound drug levels in brain, plasma and cerebrospinal fluid (CSF), and free brain concentration/free plasma concentration should be considered to accurately predict and rationalize CNS target engagement and in vivo effects rather than absolute brain penetration (e.g., B/P ratio).