Squalamine
{{distinguish|squalene}}
{{chembox
| ImageFile = Squalamine.svg
| ImageSize = 250px
| ImageAlt =
| IUPACName = (24R)-3β-({3-[(3-Aminopropyl)amino]propyl}amino)-7α-hydroxycholestan-24-yl hydrogen sulfate
| SystematicName = (3R,6R)-6-[(1R,3aS,3bR,4R,5aR,7S,9aS,9bS,11aR)-7-({3-[(3-Aminopropyl)amino]propyl}amino)-4-hydroxy-9a,11a-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-1-yl]-2-methylheptan-3-yl hydrogen sulfate
|Section1={{Chembox Identifiers
| UNII_Ref = {{fdacite|correct|FDA}}
| UNII = F8PO54Z4V7
| CASNo =148717-90-2
|KEGG=C16841
| PubChem = 72495
| ChemSpiderID = 65407
| InChI = 1/C34H65N3O5S/c1-23(2)31(42-43(39,40)41)12-9-24(3)27-10-11-28-32-29(14-16-34(27,28)5)33(4)15-13-26(21-25(33)22-30(32)38)37-20-8-19-36-18-7-6-17-35/h23-32,36-38H,6-22,35H2,1-5H3,(H,39,40,41)/t24-,25-,26+,27-,28+,29+,30-,31-,32+,33+,34-/m1/s1
| InChIKey = UIRKNQLZZXALBI-MSVGPLKSBB
| StdInChI = 1S/C34H65N3O5S/c1-23(2)31(42-43(39,40)41)12-9-24(3)27-10-11-28-32-29(14-16-34(27,28)5)33(4)15-13-26(21-25(33)22-30(32)38)37-20-8-19-36-18-7-6-17-35/h23-32,36-38H,6-22,35H2,1-5H3,(H,39,40,41)/t24-,25-,26+,27-,28+,29+,30-,31-,32+,33+,34-/m1/s1
| StdInChIKey = UIRKNQLZZXALBI-MSVGPLKSSA-N
| ChEMBL = 444929
| ChEMBL2 = 507931
| SMILES = CC(C)[C@@H](CC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3[C@H](O)C[C@H]4C[C@H](CC[C@]4(C)[C@H]3CC[C@]12C)NCCCNCCCCN)OS(=O)(=O)O}}
|Section2={{Chembox Properties
| C=34 | H=65 | N=3 | O=5 | S=1
| MolarMass = 628 g/mol
| Appearance =
| Density =
| MeltingPt =
| BoilingPt =
| Solubility = }}
|Section3={{Chembox Hazards
| MainHazards =
| FlashPt =
| AutoignitionPt = }}
}}
Squalamine was discovered in a search for anti-microbial compounds in the tissues of primitive vertebrates.doi:10.1073/pnas.90.4.1354 The team speculated that animals with primitive immune systems, such as sharks and lampreys, might utilize antimicrobial compounds as a significant component of their immune repertoire. The dogfish shark (Squalus acanthias) was the first shark species studied since it was accessible for research purposes at the Mount Desert Marine Biological Laboratory. In addition, large numbers of dogfish are harvested annually for consumption Squalus acanthias Convention on the conservation of migratory species of wild animals 2008 and could provide sufficient tissue for extraction during the early stages of compound isolation and characterization. The chemical synthesis was developed by William A. Kinney and colleagues,.doi:10.1021/jo981344zdoi:/10.1016/S0040-4039(99)00896-5
Squalamine consists of a spermidine coupled to a C-27 sulfated bile salt, a natural product with an unprecedented chemical structure.doi: 10.1073/pnas.90.4.1354 In addition 7 additional aminosterols were isolated from dogfish liver, including Trodusquemine.doi: 10.1021/np990514f Squalamine was later identified in the white blood cells of the lamprey.doi: 10.1194/jlr.M700294-JLR200
Squalamine has broad spectrum microbicidal activity,PMID 23735598PMID 18648511PMID 22998181 and its use as a therapeutic has been studied preclinically.doi: 10.1093/jac/dks230 In the late 1990’s squalamine was discovered to exhibit antiangiogenic activity,PMID 9661892PMID 15128931 and as a consequence was later studied in several early stage clinical trials for both cancer,PMID 11751482PMID 12855619 age related macular degeneration, administered intravenously,doi:10.1586/17469899.2.2.165A Phase I/II Trial of Intravenous Squalamine Lactate for Treatment of Choroidal Neovascularization in Age Related Macular Degeneration (ARMD) and as an eye-drop in combination with intraocular ranibizumab.{{cite web | url=https://www.hcplive.com/view/jason-slakter-md-squalamine-lactate-eye-drops-in-wet-amd | title=Jason Slakter, MD: Squalamine Lactate Eye Drops in Wet AMD | date=13 November 2017 }}
In aqueous solution at physiological pH squalamine exists as an amphipathic zwitterion with a net cationic charge. As a consequence the molecule is attracted by electrostatic forces to membranes that display negatively charged phospholipid headgroups, such as the intracellular membranes of animal cells. Once squalamine crosses the plasma membrane of an animal cell it binds to the cytoplasmic surface of the plasma membrane and displaces proteins that are bound electrostatically, a property that explains its inhibition of the sodium-hydrogen transporter type 3,doi: 10.1038/emboj.2010.356 neuronal synaptic AMPA receptors doi:10.1016/j.neuron.2010.04.035 and its broad spectrum antiviral activity.doi.org/10.1073/pnas.1108558108
In 2017, Perni et al reported that squalamine could displace alpha-synuclein from neuronal membranes both in vitro, in isolated cells, and in a C. elegans Parkinson disease model.doi: 10.1073/pnas.1610586114. Epub 2017 Jan 17 Since alpha synuclein accumulates within the enteric, peripheral and central nervous system of individuals suffering from Parkinson’s disease where it forms toxic aggregates damaging or killing neurons,doi: 10.1007/s00702-002-0808-2 squalamine emerged as a potential therapeutic. Studies in mouse models of Parkinson’s disease demonstrated that orally administered squalamine could restore the electrical activity of enteric neurons and thereby restore peristaltic activity, reversing constipation, a non-motor symptom of Parkinson’s disease.doi: 10.3233/JPD-202076 Squalamine also restored electrical signaling between the enteric nervous system and the brain ( the “gut-brain axis”).doi: 10.3233/JPD-202076 In addition the electrical signals induced by orally administered squalamine phenocopied those elicited by SSRI anti-depressant drugs suggesting that the compound could, via the gut-brain axis, elicit an anti-depressant effect.doi: 10.1038/s41598-021-00615-w
Based on these preclinical studies squalamine (as the phosphate salt (ENT-01)) was evaluated for the treatment of Parkinson’s disease associated constipation in two clinical trials: RASMET, an open label Phase 1b trial,doi: 10.1016/j.prdoa.2019.06.001 and subsequently, KARMET, a Phase 2a placebo controlled randomized double blinded trial involving about 150 patients.doi: 10.7326/M22-1438. Epub 2022 Nov 8 Both trials, conducted by Enterin, Inc (Philadelphia) demonstrated that a 28 day course of orally administered ENT-03 effectively corrected constipation that had been previously intractable. In addition, positive efficacy signals were seen in circadian rhythm and sleep, dementia and hallucinations. ENT-01 is now (2024) positioned for Phase 3 clinical trials.