TCP-FA4: A derivative of tranylcypromine showing improved blood-brain permeability

A variety of approaches have been taken to improve the brain penetration of pharmaceutical agents. Theamphipathic character of a compound can improve its interaction with the lipid bilayer within cellmembranes, and as a result improve permeability. Fatty acid chains or lipoamino acids of various lengthswere attached to tranylcypromine (TCP), in an attempt to improve the blood–brain barrier (BBB)permeability by increasing the lipophilicity as well as the amphiphatic character of the drug. TCP-FA4,one of the derivatives containing a four carbon alkyl acid chain, showed the greatest improvement inpermeability. This molecule was slightly neuroprotective in a b-amyloid-induced neurodegenerationassay and may also be capable of upregulating brain derived neurotrophic factor (BDNF), as indicated bycell culture assays using human umbilical vein endothelial cells. Since decreased levels of BDNF areobserved in many CNS disorders, and direct injection of BDNF is not a viable option due to its poorpermeability across the BBB, small molecules capable of regulating BDNF that also cross the BBB may bean interesting treatment option.