title: TCP-FA4: a derivative of tranylcypromine showing improved blood-brain permeability.
abstract: A variety of approaches have been taken to improve the brain penetration of pharmaceutical agents. The amphipathic character of a compound can improve its interaction with the lipid bilayer within cell membranes, and as a result improve permeability. Fatty acid chains or lipoamino acids of various lengths were 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 in permeability. This molecule was slightly neuroprotective in a beta-amyloid-induced neurodegeneration assay and may also be capable of upregulating brain derived neurotrophic factor (BDNF), as indicated by cell culture assays using human umbilical vein endothelial cells. Since decreased levels of BDNF are observed in many CNS disorders, and direct injection of BDNF is not a viable option due to its poor permeability across the BBB, small molecules capable of regulating BDNF that also cross the BBB may be an interesting treatment option.
authors.affiliation: The University of Kansas, Department of Pharmaceutical Chemistry, 2095 Constant Ave, Lawrence, KS 66047, USA. Kelly.Desino@abbott.com
authors.forename: Kelly E
authors.initials: KE
authors.lastname: Desino
authors.forename: Rosario
authors.initials: R
authors.lastname: Pignatello
authors.forename: Salvatore
authors.initials: S
authors.lastname: Guccione
authors.forename: Livia
authors.initials: L
authors.lastname: Basile
authors.forename: Sabah
authors.initials: S
authors.lastname: Ansar
authors.forename: Mary Lou
authors.initials: ML
authors.lastname: Michaelis
authors.forename: Rona R
authors.initials: RR
authors.lastname: Ramsay
authors.forename: Kenneth L
authors.initials: KL
authors.lastname: Audus
mesh_terms: D016229:Amyloid beta-Peptides / Q000494:pharmacology; D000818:Animals; D001812:Blood-Brain Barrier / Q000166:cytology / Q000378:metabolism*; D001921:Brain / Q000098:blood supply; D019208:Brain-Derived Neurotrophic Factor / Q000096:biosynthesis; D002417:Cattle; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D004730:Endothelium, Vascular / Q000166:cytology; D006801:Humans; D055806:Microvessels / Q000166:cytology; D008996:Monoamine Oxidase Inhibitors / Q000493:pharmacokinetics / Q000494:pharmacology; D009474:Neurons / Q000166:cytology / Q000187:drug effects; D018696:Neuroprotective Agents / Q000493:pharmacokinetics* / Q000494:pharmacology; D010446:Peptide Fragments / Q000494:pharmacology; D010539:Permeability; D051381:Rats; D017207:Rats, Sprague-Dawley; D014191:Tranylcypromine / Q000031:analogs & derivatives* / Q000493:pharmacokinetics* / Q000494:pharmacology; D014471:Umbilical Veins / Q000166:cytology; D015854:Up-Regulation
chemical_list: D016229:Amyloid beta-Peptides; D019208:Brain-Derived Neurotrophic Factor; D008996:Monoamine Oxidase Inhibitors; D018696:Neuroprotective Agents; D010446:Peptide Fragments; C074636:amyloid beta-protein (25-35); C544437:tranylcypromine-FA4; D014191:Tranylcypromine