title: Small-molecule modulation of neurotrophin receptors: a strategy for the treatment of neurological disease.
abstract: Neurotrophins and their receptors modulate multiple signalling pathways to regulate neuronal survival and to maintain axonal and dendritic networks and synaptic plasticity. Neurotrophins have potential for the treatment of neurological diseases. However, their therapeutic application has been limited owing to their poor plasma stability, restricted nervous system penetration and, importantly, the pleiotropic actions that derive from their concomitant binding to multiple receptors. One strategy to overcome these limitations is to target individual neurotrophin receptors — such as tropomyosin receptor kinase A (TRKA), TRKB, TRKC, the p75 neurotrophin receptor or sortilin — with small-molecule ligands. Such small molecules might also modulate various aspects of these signalling pathways in ways that are distinct from the programmes triggered by native neurotrophins. By departing from conventional neurotrophin signalling, these ligands might provide novel therapeutic options for a broad range of neurological indications.
authors: Department of Neurology and Neurological Sciences, Stanford University, 300 Pasteur Drive, Stanford, California 94305, USA. longo@stanford.edu
authors: Frank M
authors: FM
authors: Longo
authors: Stephen M
authors: SM
authors: Massa
mesh_terms: D000818:Animals; D002986:Clinical Trials as Topic; D055808:Drug Discovery / Q000379:methods*; D006801:Humans; D008024:Ligands; D058990:Molecular Targeted Therapy / Q000379:methods*; D009414:Nerve Growth Factors / Q000096:biosynthesis / Q000378:metabolism / Q000627:therapeutic use; D009422:Nervous System Diseases / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D017475:Receptors, Nerve Growth Factor / Q000378:metabolism*; D015398:Signal Transduction; D054852:Small Molecule Libraries / Q000494:pharmacology / Q000627:therapeutic use*
chemical_list: D008024:Ligands; D009414:Nerve Growth Factors; D017475:Receptors, Nerve Growth Factor; D054852:Small Molecule Libraries
references: Somatosens Mot Res. 1995;12(3-4):329-42
references: 8834306
references: Science. 2003 May 2;300(5620):750-2
references: 12730587
references: Invest Ophthalmol Vis Sci. 2010 Sep;51(9):4722-31
references: 20357199
references: J Cell Sci. 2009 Sep 15;122(Pt 18):3351-7
references: 19706676
references: Science. 1999 May 7;284(5416):974-7
references: 10320380
references: J Neurochem. 2013 May;125(3):386-98
references: 23350698
references: J Med Chem. 2002 Sep 26;45(20):4387-90
references: 12238916
references: J Neurosci Res. 2009 Jun;87(8):1892-903
references: 19156869
references: Prog Neurobiol. 2003 Apr;69(5):341-74
references: 12787574
references: J Biol Chem. 2000 Sep 22;275(38):29868-74
references: 10896671
references: J Med Chem. 2010 Dec 9;53(23):8274-86
references: 21073191
references: J Neuropathol Exp Neurol. 2010 Feb;69(2):139-54
references: 20084019
references: Clin Sci (Lond). 2006 Feb;110(2):167-73
references: 16411893
references: Cereb Cortex. 1993 Mar-Apr;3(2):133-47
references: 8490319
references: Dement Geriatr Cogn Disord. 1998 Sep-Oct;9(5):246-57
references: 9701676
references: Biochemistry. 2002 Dec 3;41(48):14263-71
references: 12450391
references: Brain Res. 1992 Aug 28;589(1):115-23
references: 1422811
references: Science. 1999 Feb 12;283(5404):987-90
references: 9974392
references: J Biol Chem. 1998 Dec 25;273(52):34933-40
references: 9857023
references: Nat Neurosci. 2002 Dec;5(12):1302-8
references: 12426574
references: J Neurochem. 2008 Nov;107(4):1124-35
references: 18808449
references: Nat Med. 2009 Mar;15(3):331-7
references: 19198615
references: Neurotox Res. 2010 Apr;17(3):257-67
references: 19680737
references: Mol Pharmacol. 2011 Sep;80(3):498-508
references: 21616921
references: Brain Res. 2000 Jan 24;853(2):174-85
references: 10640615
references: Curr Med Chem. 2009;16(11):1355-65
references: 19355891
references: J Cell Biol. 1997 Jan 27;136(2):375-88
references: 9015308
references: Annu Rev Neurosci. 2001;24:1217-81
references: 11520933
references: PLoS One. 2013;8(1):e53596
references: 23320097
references: Nat Neurosci. 2005 Aug;8(8):1069-77
references: 16025106
references: J Biol Chem. 2008 Nov 28;283(48):33375-83
references: 18809686
references: Curr Biol. 1999 Jul 29-Aug 12;9(15):R568-71
references: 10469554
references: Cytokine Growth Factor Rev. 2003 Jun-Aug;14(3-4):225-39
references: 12787561
references: J Neurosci. 2011 Sep 7;31(36):12889-99
references: 21900567
references: Proc Natl Acad Sci U S A. 2012 Feb 28;109(9):3540-5
references: 22331903
references: Curr Opin Investig Drugs. 2002 Dec;3(12):1753-7
references: 12528312
references: Pharm Res. 1999 Feb;16(2):232-40
references: 10100308
references: Neurosci Lett. 2011 Jun 27;497(3):172-6
references: 21354270
references: Nature. 2004 Feb 26;427(6977):843-8
references: 14985763
references: J Neurosci. 2012 Jan 11;32(2):703-12
references: 22238106
references: Proc Natl Acad Sci U S A. 2010 Feb 9;107(6):2687-92
references: 20133810
references: Proc Natl Acad Sci U S A. 2007 Oct 9;104(41):16329-34
references: 17911251
references: Pain. 1999 Jan;79(1):21-29
references: 9928772
references: J Med Chem. 2012 Oct 11;55(19):8524-37
references: 22984948
references: J Biol Chem. 2001 Jun 22;276(25):23097-104
references: 11312266
references: Biochem Biophys Res Commun. 1995 Dec 14;217(2):488-94
references: 7503726
references: Dev Neurobiol. 2007 Jun;67(7):884-94
references: 17506493
references: J Neurochem. 2004 Apr;89(2):344-53
references: 15056278
references: Sci Signal. 2013 Feb 12;6(262):pe6
references: 23405011
references: Exp Neurol. 2010 Aug;224(2):495-506
references: 20553714
references: J Neurochem. 1998 Apr;70(4):1712-21
references: 9523590
references: J Mol Signal. 2012 Jan 24;7(1):2
references: 22269274
references: Am J Psychiatry. 2011 Feb;168(2):163-72
references: 21123312
references: Neurosci Lett. 2011 Jul 25;499(3):181-5
references: 21651962
references: Prog Neurobiol. 2012 Aug;98(2):197-206
references: 22705453
references: Anat Rec. 1994 Dec;240(4):579-88
references: 7879909
references: J Neurochem. 2008 Apr;105(2):369-79
references: 18086127
references: J Neurosci. 2008 Mar 12;28(11):2698-709
references: 18337399
references: Clin Sci (Lond). 2006 Feb;110(2):175-91
references: 16411894
references: J Biol Chem. 1993 Oct 5;268(28):21410-5
references: 8407983
references: J Biol Chem. 1998 May 1;273(18):11197-204
references: 9556609
references: FEBS Lett. 2011 Jan 21;585(2):295-9
references: 21187090
references: Physiol Behav. 2011 Feb 1;102(2):149-57
references: 21059364
references: Science. 1999 Feb 12;283(5404):990-3
references: 9974393
references: Oncogene. 2001 Mar 8;20(10):1229-34
references: 11313867
references: Proc Natl Acad Sci U S A. 2006 Apr 25;103(17):6735-40
references: 16618925
references: Prog Neurobiol. 2002 Jun;67(3):203-33
references: 12169297
references: Clin Cancer Res. 2009 May 15;15(10):3244-50
references: 19417027
references: J Biol Chem. 2009 Jul 3;284(27):18424-33
references: 19389705
references: Ann N Y Acad Sci. 2005 Aug;1053:247-57
references: 16179530
references: J Mol Biol. 2010 Mar 5;396(4):967-84
references: 20036257
references: J Neuropathol Exp Neurol. 2012 Nov;71(11):1018-29
references: 23095849
references: Nat Neurosci. 2004 Mar;7(3):221-8
references: 14966521
references: Mol Cell. 2011 Nov 4;44(3):476-90
references: 22055192
references: J Neuropathol Exp Neurol. 2004 Jun;63(6):641-9
references: 15217092
references: J Neurosci Res. 1997 Apr 1;48(1):1-17
references: 9086177
references: J Invest Dermatol. 2003 Jan;120(1):168-9
references: 12535214
references: J Neurochem. 2013 Feb;124(3):276-89
references: 23157347
references: Neuropsychopharmacology. 2012 Jan;37(2):434-44
references: 21900882
references: Curr Drug Targets CNS Neurol Disord. 2002 Feb;1(1):59-80
references: 12769635
references: Eur J Neurosci. 2006 Sep;24(6):1575-80
references: 17004921
references: J Biol Chem. 2013 Apr 19;288(16):11144-54
references: 23471969
references: J Neurosci Res. 2000 Feb 1;59(3):402-9
references: 10679776
references: Neurology. 1999 Apr 22;52(7):1427-33
references: 10227630
references: Proteins. 2012 Mar;80(3):703-12
references: 22189720
references: PLoS One. 2010 Jul 13;5(7):e11528
references: 20644624
references: J Mol Neurosci. 2010 Jan;40(1-2):230-5
references: 19680822
references: Neurobiol Dis. 2011 Apr;42(1):35-47
references: 21220014
references: Science. 1994 Sep 9;265(5178):1596-9
references: 8079174
references: J Biol Chem. 2003 Jul 11;278(28):25738-44
references: 12730196
references: Biophys J. 2002 Aug;83(2):968-76
references: 12124278
references: Neuron. 2007 Jan 4;53(1):1-4
references: 17196523
references: Nature. 2008 Aug 7;454(7205):789-93
references: 18596692
references: J Pharmacol Sci. 2003 Apr;91(4):267-70
references: 12719654
references: Cell Death Dis. 2012 Sep 06;3:e389
references: 22951986
references: J Neurosci. 2006 Jul 19;26(29):7756-66
references: 16855103
references: Prog Neurobiol. 2006 Oct;80(2):53-83
references: 17030082
references: Neurochem Int. 2012 Dec;61(8):1266-75
references: 23103525
references: Nature. 1996 Oct 24;383(6602):716-9
references: 8878481
references: Cell. 2004 Jul 9;118(1):127-38
references: 15242649
references: JAMA. 2000 Nov 1;284(17):2215-21
references: 11056593
references: Proc Natl Acad Sci U S A. 2007 Aug 14;104(33):13361-6
references: 17686986
references: J Clin Invest. 2010 May;120(5):1774-85
references: 20407211
references: Brain Res Mol Brain Res. 1996 Mar;36(2):280-6
references: 8965648
references: ACS Chem Biol. 2009 Sep 18;4(9):769-81
references: 19735123
references: Mol Cell Biol. 2000 Aug;20(16):5908-16
references: 10913174
references: Cytokine Growth Factor Rev. 2012 Feb-Apr;23(1-2):15-24
references: 22341689
references: J Cell Biol. 2007 Jun 18;177(6):1119-32
references: 17576803
references: J Biol Chem. 2001 Aug 31;276(35):32687-95
references: 11435417
references: Traffic. 2007 Dec;8(12):1736-1749
references: 17897318
references: Neuroscience. 2008 Jun 26;154(3):978-93
references: 18511210
references: Chem Biol. 2009 Jun 26;16(6):644-56
references: 19549602
references: J Am Chem Soc. 2008 Jan 16;130(2):556-65
references: 18088119
references: Mol Cell. 2003 Feb;11(2):507-17
references: 12620237
references: Mol Ther. 2005 Aug;12(2):307-13
references: 15927533
references: J Neurosci Res. 2001 Sep 1;65(5):463-9
references: 11536331
references: Annu Rev Biochem. 2003;72:609-42
references: 12676795
references: Nat Rev Neurosci. 2001 Jan;2(1):24-32
references: 11253356
references: Neurology. 1997 Feb;48(2):501-5
references: 9040746
references: Hippocampus. 2012 Mar;22(3):399-408
references: 21136519
references: Dev Neurobiol. 2010 Feb 15;70(3):150-64
references: 19953569
references: Front Physiol. 2012 Dec 20;3:464
references: 23267328
references: Neurology. 2001 Oct 9;57(7):1313-6
references: 11591856
references: J Neurosci. 2004 Sep 15;24(37):8009-18
references: 15371501
references: Am J Physiol Endocrinol Metab. 2012 May 1;302(10):E1252-60
references: 22374757
references: Neuron. 2006 Feb 2;49(3):341-8
references: 16446138
references: J Pharmacol Exp Ther. 2007 Jul;322(1):59-69
references: 17468299
references: Mol Pharmacol. 2000 Feb;57(2):385-91
references: 10648649
references: Neurotoxicology. 2008 Jul;29(4):605-12
references: 18539332
references: J Biol Chem. 2007 Mar 9;282(10):7606-15
references: 17215246
references: Science. 1993 Jul 16;261(5119):345-8
references: 8332899
references: Neuron. 1994 May;12(5):1161-71
references: 7514427
references: Bioessays. 2011 Aug;33(8):614-25
references: 21717487
references: J Cell Biol. 2001 Dec 24;155(7):1275-85
references: 11756477
references: PLoS One. 2008;3(11):e3604
references: 18978948
references: Eur J Neurosci. 2006 Oct;24(7):1857-66
references: 17040478
references: J Biol Chem. 2000 Aug 11;275(32):24414-20
references: 10825163
references: Mol Cell Neurosci. 2009 Apr;40(4):410-20
references: 19146958
references: Proc Natl Acad Sci U S A. 2007 Feb 20;104(8):2985-90
references: 17301229
references: J Neurochem. 2004 May;89(3):581-92
references: 15086515
references: Ann N Y Acad Sci. 1995 Sep 7;766:442-58
references: 7486690
references: Cell Death Differ. 1998 May;5(5):365-71
references: 10200485
references: J Peripher Nerv Syst. 2001 Dec;6(4):204-10
references: 11800042
references: J Neurosci. 2006 May 17;26(20):5288-300
references: 16707781
references: Prog Brain Res. 2000;128:333-47
references: 11105692
references: PLoS One. 2011 Feb 28;6(2):e17321
references: 21387003
references: Neurosci Res. 2009 Sep;65(1):11-22
references: 19523993
references: Exp Neurol. 1997 May;145(1):245-52
references: 9184126
references: Bioorg Med Chem Lett. 2001 Jan 22;11(2):207-10
references: 11206460
references: J Neurosci. 2006 Sep 20;26(38):9713-21
references: 16988042
references: Science. 2004 May 7;304(5672):870-5
references: 15131306
references: Structure. 2001 Dec;9(12):1191-9
references: 11738045
references: Cell. 1992 Apr 17;69(2):329-41
references: 1314703
references: Proc Natl Acad Sci U S A. 2012 Sep 25;109(39):15924-9
references: 23019376
references: J Cell Sci. 2010 Jul 1;123(Pt 13):2299-307
references: 20530577
references: Stroke. 2012 Jul;43(7):1918-24
references: 22535263
references: Neurobiol Aging. 2013 Aug;34(8):2052-63
references: 23545424
references: Neuron. 2002 Oct 24;36(3):375-86
references: 12408842
references: Epilepsia. 2009 Feb;50 Suppl 2:30-40
references: 19187292
references: PLoS One. 2010 Mar 19;5(3):e9777
references: 20333308
references: Pharmacol Biochem Behav. 2013 May;106:124-7
references: 23567202
references: Neuropathol Appl Neurobiol. 2007 Oct;33(5):533-43
references: 17596181
references: Neuron. 2007 Jan 4;53(1):25-38
references: 17196528
references: Neuron. 2004 Jul 8;43(1):31-42
references: 15233915
references: J Cell Biol. 1998 Feb 23;140(4):911-23
references: 9472042
references: Neurology. 2000 Mar 14;54(5):1080-8
references: 10720278
references: Mol Cell Neurosci. 2001 Aug;18(2):210-20
references: 11520181
references: Nature. 1999 Sep 9;401(6749):184-8
references: 10490030
references: Exp Neurol. 2007 Apr;204(2):832-5
references: 17270174
references: Neurosci Lett. 1998 Oct 16;255(2):87-90
references: 9835221
references: J Neurosci. 1995 Jan;15(1 Pt 2):477-91
references: 7823156
references: Exp Neurol. 2001 Jun;169(2):351-63
references: 11358448
references: Neurobiol Dis. 2009 May;34(2):199-211
references: 19217433
references: Proc Natl Acad Sci U S A. 2010 Feb 23;107(8):3876-81
references: 20133677
references: Nature. 2002 Nov 7;420(6911):74-8
references: 12422217
references: Proc Natl Acad Sci U S A. 1992 Apr 1;89(7):3060-4
references: 1313578
references: J Comp Neurol. 1993 Jan 15;327(3):359-75
references: 8440771
references: J Neurosci. 1998 May 1;18(9):3273-81
references: 9547236
references: J Biol Chem. 2003 Oct 24;278(43):42161-9
references: 12913006
references: J Comp Neurol. 2009 Sep 1;516(1):49-58
references: 19565663
references: J Biol Chem. 2010 Dec 10;285(50):39392-400
references: 20943663
references: Cell. 1994 May 20;77(4):503-12
references: 7514502
references: J Neurosci. 2003 Apr 15;23(8):3209-20
references: 12716928
references: J Clin Invest. 2011 May;121(5):1846-57
references: 21505263
references: Mol Cell Neurosci. 2005 Jun;29(2):162-72
references: 15911341
references: J Appl Physiol (1985). 2012 Mar;112(5):704-10
references: 22194327
references: J Clin Invest. 1997 Nov 1;100(9):2333-40
references: 9410912
references: Philos Trans R Soc Lond B Biol Sci. 2006 Sep 29;361(1473):1545-64
references: 16939974
references: Proc Natl Acad Sci U S A. 2004 Apr 20;101(16):6226-30
references: 15026568
references: J Mol Neurosci. 2005;25(2):141-56
references: 15784962
references: Science. 1996 Apr 26;272(5261):542-5
references: 8614802
references: J Biol Chem. 2003 Jul 18;278(29):26604-11
references: 12734179
references: Science. 1995 Jan 20;267(5196):383-6
references: 7529940
references: J Neuroimmune Pharmacol. 2012 Jun;7(2):388-400
references: 22161560
references: J Biol Chem. 2000 Apr 7;275(14):9946-56
references: 10744669
references: Neuron. 1998 Aug;21(2):335-45
references: 9728915
references: Dev Neurobiol. 2008 Sep 1;68(10):1243-56
references: 18563704
references: J Neurosci. 2012 Feb 1;32(5):1803-10
references: 22302819
references: J Biol Chem. 2002 Mar 8;277(10):7720-5
references: 11756426
references: Curr Opin Neurobiol. 2002 Jun;12(3):268-74
references: 12049932
references: CNS Neurol Disord Drug Targets. 2008 Feb;7(1):63-70
references: 18289033
references: Eur J Pain. 2012 Aug;16(7):953-65
references: 22337615
references: Nat Rev Neurosci. 2003 Apr;4(4):299-309
references: 12671646
references: Prog Neurobiol. 2010 Dec;92(4):505-16
references: 20713125
references: Curr Pharm Des. 2002;8(24):2201-16
references: 12369863
references: Exp Eye Res. 2011 Oct;93(4):503-12
references: 21726552
references: J Neurosci. 2011 Dec 7;31(49):17800-10
references: 22159096
references: J Neurosci. 2013 Jan 9;33(2):397-410
references: 23303920
references: Cell Regul. 1990 Jan;1(2):189-95
references: 2100197
references: Neuron. 1999 Nov;24(3):585-93
references: 10595511
references: Sci Signal. 2011 Dec 06;4(202):ra82
references: 22155786
references: Trends Neurosci. 1998 Oct;21(10):438-44
references: 9786342
references: Nat Neurosci. 2002 Nov;5 Suppl:1046-50
references: 12403983
references: J Mol Biol. 2011 Dec 16;414(5):681-98
references: 21978666
references: J Biol Chem. 1995 Mar 24;270(12):6564-9
references: 7896793
references: Proc Natl Acad Sci U S A. 1997 Sep 2;94(18):9909-14
references: 9275225
references: J Biol Chem. 2010 Apr 16;285(16):12210-22
references: 20159974
references: Mol Neurodegener. 2009 Nov 23;4:48
references: 19930651