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

Kelly E. Desino; Rosario Pignatello; Salvatore Guccione; Livia Basile; Sabah Ansar; Mary Lou Michaelis; Rona R. Ramsay; Kenneth L. Audus

doi:10.1016/j.bcp.2009.07.027

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

Kelly E. Desino, Rosario Pignatello, Salvatore Guccione, Livia Basile, Sabah Ansar, Mary Lou Michaelis, Rona R. Ramsay, Kenneth L. Audus

Research output: Contribution to journal › Article › peer-review

8 Citations (Scopus)

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 P-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. (C) 2009 Elsevier Inc. All rights reserved.

Original language	English
Pages (from-to)	1412-1417
Number of pages	6
Journal	Biochemical Pharmacology
Volume	78
Issue number	11
DOIs	https://doi.org/10.1016/j.bcp.2009.07.027
Publication status	Published - 1 Dec 2009

Keywords

Fatty acid chains
Lipoamino acids
Blood-brain barrier (BBB)
Neuroprotection
beta-Amyloid
Monoamine oxidase inhibition
P-GLYCOPROTEIN
MONOAMINE-OXIDASE
CELL-MEMBRANES
FUNCTIONAL-ACTIVITY
NEUROTROPHIC FACTOR
ENDOTHELIAL-CELLS
LIPOAMINO ACIDS
DRUG AFFINITY
ENHANCEMENT
TRANSPORT

Access to Document

10.1016/j.bcp.2009.07.027

Cite this

@article{097f4d0c73124b31ab2409d7932f1c8e,

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 P-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. (C) 2009 Elsevier Inc. All rights reserved.",

keywords = "Fatty acid chains, Lipoamino acids, Blood-brain barrier (BBB), Neuroprotection, beta-Amyloid, Monoamine oxidase inhibition, P-GLYCOPROTEIN, MONOAMINE-OXIDASE, CELL-MEMBRANES, FUNCTIONAL-ACTIVITY, NEUROTROPHIC FACTOR, ENDOTHELIAL-CELLS, LIPOAMINO ACIDS, DRUG AFFINITY, ENHANCEMENT, TRANSPORT",

author = "Desino, {Kelly E.} and Rosario Pignatello and Salvatore Guccione and Livia Basile and Sabah Ansar and Michaelis, {Mary Lou} and Ramsay, {Rona R.} and Audus, {Kenneth L.}",

year = "2009",

month = dec,

day = "1",

doi = "10.1016/j.bcp.2009.07.027",

language = "English",

volume = "78",

pages = "1412--1417",

journal = "Biochemical Pharmacology",

issn = "0006-2952",

publisher = "Elsevier Inc.",

number = "11",

}

TY - JOUR

T1 - TCP-FA4: A derivative of tranylcypromine showing improved blood-brain permeability

AU - Desino, Kelly E.

AU - Pignatello, Rosario

AU - Guccione, Salvatore

AU - Basile, Livia

AU - Ansar, Sabah

AU - Michaelis, Mary Lou

AU - Ramsay, Rona R.

AU - Audus, Kenneth L.

PY - 2009/12/1

Y1 - 2009/12/1

N2 - 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 P-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. (C) 2009 Elsevier Inc. All rights reserved.

AB - 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 P-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. (C) 2009 Elsevier Inc. All rights reserved.

KW - Fatty acid chains

KW - Lipoamino acids

KW - Blood-brain barrier (BBB)

KW - Neuroprotection

KW - beta-Amyloid

KW - Monoamine oxidase inhibition

KW - P-GLYCOPROTEIN

KW - MONOAMINE-OXIDASE

KW - CELL-MEMBRANES

KW - FUNCTIONAL-ACTIVITY

KW - NEUROTROPHIC FACTOR

KW - ENDOTHELIAL-CELLS

KW - LIPOAMINO ACIDS

KW - DRUG AFFINITY

KW - ENHANCEMENT

KW - TRANSPORT

U2 - 10.1016/j.bcp.2009.07.027

DO - 10.1016/j.bcp.2009.07.027

M3 - Article

SN - 0006-2952

VL - 78

SP - 1412

EP - 1417

JO - Biochemical Pharmacology

JF - Biochemical Pharmacology

IS - 11

ER -

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

Abstract

Keywords

Access to Document

Fingerprint

Cite this