Ferruginine

{{Infobox drug | drug_name = Ferruginine | image = Ferruginine v2.svg | width = 150px | caption = (+)-Ferruginine

| legal_status =

| IUPAC_name = 1-(8-Methyl-8-azabicyclo[3.2.1]oct-2-en-2-yl)ethanone | C=10 | H=15 | N=1 | O=1 | SMILES = CC(=O)C1=CCC2CCC1N2C | StdInChI = 1S/C10H15NO/c1-7(12)9-5-3-8-4-6-10(9)11(8)2/h5,8,10H,3-4,6H2,1-2H3 | StdInChIKey = KQIRSQYBYQBMIG-UHFFFAOYSA-N }}

'''Ferruginine''' is a naturally occurring tropane alkaloid isolated from rainforest tree species such as ''Darlingia ferruginea'' and ''Darlingia darlingiana''.<ref name="Yin_2018">{{cite journal | vauthors = Yin Z, He Y, Chiu P | title = Application of (4+3) cycloaddition strategies in the synthesis of natural products | journal = Chemical Society Reviews | volume = 47 | issue = 23 | pages = 8881–8924 | date = November 2018 | pmid = 30394457 | doi = 10.1039/c8cs00532j }}</ref> It acts as a nicotinic acetylcholine receptor (nAchR) agonist.<ref name="Daly_2005" /><ref>{{cite journal | vauthors = Seifert S, Stehl A, Tilotta MC, Gündisch D, Seitz G | title = Novel enantiopure ferrugininoids active as nicotinic agents: synthesis and radioligand binding studies | journal = Die Pharmazie | volume = 59 | issue = 6 | pages = 427–434 | date = June 2004 | pmid = 15248455 }}</ref> Nicotinic agonists have been studied for their possible roles in cognitive enhancement and in the treatment of neurodegenerative diseases.<ref name="Crestini_2024">{{cite journal | vauthors = Crestini A, Carbone E, Rivabene R, Ancidoni A, Rosa P, Tata AM, Fabrizi E, Locuratolo N, Vanacore N, Lacorte E, Piscopo P | title = A Systematic Review on Drugs Acting as Nicotinic Acetylcholine Receptor Agonists in the Treatment of Dementia | journal = Cells | volume = 13 | issue = 3 | date = January 2024 | page = 237 | pmid = 38334629 | pmc = 10854606 | doi = 10.3390/cells13030237 | doi-access = free }}</ref>

Ferruginine is structurally related to methylecgonidine, but it contains a keto group in place of the ester. This substitution is advantageous because, unlike an ester, the keto group cannot be hydrolyzed into a carboxylic acid, a process that commonly leads to metabolic deactivation. (+)-Ferruginine is the natural enantiomer, with a reported specific rotation of <math>[\alpha]_D^{19} = +37</math>° (CHCl3).<ref name = "Katoh_2002" />

Ferruginine has long been a target in total synthesis research, with efforts directed at both its natural (+) and unnatural (−) enantiomers.<ref name="Yin_2018" /> The natural (+)-ferruginine<ref name="Daly_2005">{{cite journal | vauthors = Daly JW | title = Nicotinic agonists, antagonists, and modulators from natural sources | journal = Cellular and Molecular Neurobiology | volume = 25 | issue = 3–4 | pages = 513–552 | date = June 2005 | pmid = 16075378 | pmc = 11529529 | doi = 10.1007/s10571-005-3968-4 }}</ref><ref>{{cite journal | vauthors = Gohlke H, Gündisch D, Schwarz S, Seitz G, Tilotta MC, Wegge T | title = Synthesis and nicotinic binding studies on enantiopure diazine analogues of the novel (2-chloro-5-pyridyl)-9-azabicyclo[4.2.1]non-2-ene UB-165 | journal = Journal of Medicinal Chemistry | volume = 45 | issue = 5 | pages = 1064–1072 | date = February 2002 | pmid = 11855986 | doi = 10.1021/jm010936y }}</ref> acts as a potent agonist of the nicotinic acetylcholine receptor (nAchR).<ref name="Daly_2005" /><ref>{{cite journal | vauthors = Seifert S, Stehl A, Tilotta MC, Gündisch D, Seitz G | title = Novel enantiopure ferrugininoids active as nicotinic agents: synthesis and radioligand binding studies | journal = Die Pharmazie | volume = 59 | issue = 6 | pages = 427–434 | date = June 2004 | pmid = 15248455 }}</ref> By contrast, the unnatural (−)-enantiomer exhibits much lower affinity for nAchR. The distinctive structural features and pharmacological properties of ferruginine and its analogues have made them attractive scaffolds for synthetic studies.<ref>{{cite journal | vauthors = Pollini GP, Benetti S, De Risi C, Zanirato V | title = Synthetic approaches to enantiomerically pure 8-azabicyclo[3.2.1]octane derivatives | journal = Chemical Reviews | volume = 106 | issue = 6 | pages = 2434–2454 | date = June 2006 | pmid = 16771455 | doi = 10.1021/cr050995+ }}</ref>

== Pharmacology ==

The natural (+)-ferruginine exhibits high affinity for the α4β2 subtype of nicotinic acetylcholine receptors (nAChRs), with Ki values reported as low as 3.7 nM in structure-activity studies, indicating strong potency and preference for this receptor subtype.<ref>{{cite thesis | vauthors = Tilotta MC | title = Novel Nicotinic Acetylcholine Receptor Ligands based on Cytisine, Ferruginine, Anatoxin-a and Choline | degree = Ph.D. | publisher = Universitäts-und Landesbibliothek Bonn | url = https://bonndoc.ulb.uni-bonn.de/xmlui/handle/20.500.11811/2112 }}</ref> In contrast, the synthetic (−)-ferruginine shows moderate affinity for α4β2 nAChRs, with Ki values in the 94–120 nM range, and a weaker affinity (about 270 nM) for the α7 subtype.<ref name="Gündisch_2001">{{cite journal | vauthors = Gündisch D, Harms K, Schwarz S, Seitz G, Stubbs MT, Wegge T | title = Synthesis and evaluation of diazine containing bioisosteres of (-)-ferruginine as ligands for nicotinic acetylcholine receptors | journal = Bioorganic & Medicinal Chemistry | volume = 9 | issue = 10 | pages = 2683–91 | date = October 2001 | pmid = 11557356 | doi = 10.1016/s0968-0896(01)00188-2 }}</ref> Both enantiomers demonstrate significantly lower affinity for α7 nAChRs, but overall, (+)-ferruginine, the natural form, is pharmacologically distinguished by its high affinity and selectivity for central α4β2 nAChRs.

== Synthesis == The synthesis of ferruginine has been accomplished through a variety of strategies, reflecting its importance as a structurally complex tropane alkaloid. One of the earliest and most efficient approaches employed a tandem cyclopropanation / Cope rearrangement sequence catalyzed by dirhodium(II) tetraoctanoate (Rh2(oct)4), which afforded racemic ferruginine in yields of up to 96%.<ref>{{cite journal | vauthors = Davies HM, Saikali E, Young WB | title = Synthesis of (.+-.)-ferruginine and (.+-.)-anhydroecgonine methyl-ester by a tandem cyclopropanation/Cope rearrangement | journal = The Journal of Organic Chemistry | volume = 56 | issue = 19 | pages = 5696–5700 | date = September 1991 | doi = 10.1021/jo00019a044 }}</ref>

center|500px|Ferruginine synthesis

A related method based on a BF3-induced rearrangement of aziridino cyclopropanes achieved comparable yields (~90%).<ref>{{cite journal | vauthors = Jonsson SY, Löfström CM, Bäckvall JE | title = BF(3)-Induced rearrangement of aziridino cyclopropanes derived from 2-phenylsulfonyl 1,3-dienes. Application to the total synthesis of (+/-)-ferruginine | journal = The Journal of Organic Chemistry | volume = 65 | issue = 25 | pages = 8454–8457 | date = December 2000 | pmid = 11112563 | doi = 10.1021/jo001147b }}</ref> Subsequent work has expanded the synthetic toolbox to include enantioselective routes from chiral pool precursors such as L-glutamic acid,<ref name = "Hernández_1996">{{cite journal | vauthors = Hernández AS, Thaler A, Castells J, Rapoport H | title = Enantiospecific Synthesis of (+)- and (−)-Ferruginine from l -Glutamic Acid. Synthesis of Tropanes via Intramolecular Iminium Ion Cyclization | journal = The Journal of Organic Chemistry | volume = 61 | issue = 1 | pages = 314–323 | date = 1 January 1996 | doi = 10.1021/jo9515081 }}</ref> catalytic asymmetric dealkoxycarbonylation strategies using pig liver esterase (PLE),<ref name = "Katoh_2002">{{cite journal | vauthors = Katoh T, Kakiya K, Nakai T, Nakamura S, Nishide K, Node M | title = A new divergent synthesis of (+)- and (−)-ferruginine utilizing PLE-catalyzed asymmetric dealkoxycarbonylation | journal = Tetrahedron: Asymmetry | volume = 13 | issue = 21 | pages = 2351–2358 | date = October 2002 | doi = 10.1016/S0957-4166(02)00657-2 }}</ref> and intramolecular iminium ion cyclizations.<ref name="Hernández_1996" /> Other formal and total syntheses have employed strategies such as palladium-catalyzed intramolecular aminocarbonylation,<ref>{{cite journal | vauthors = Ham WH, Jung YH, Lee K, Oh CY, Lee KY | title = A formal total synthesis of (±)-ferruginine by Pd-catalyzed intramolecular aminocarbonylation | journal = Tetrahedron Letters | volume = 38 | issue = 18 | pages = 3247–3248 | date = May 1997 | doi = 10.1016/S0040-4039(97)00575-3 }}</ref> radical-based methodologies,<ref>{{cite journal | vauthors = Piccardi R, Renaud P | title = Formal Synthesis of (+)- and (–)-Ferruginine | journal = European Journal of Organic Chemistry | volume = 2007 | issue = 28 | pages = 4752–4757 | date = October 2007 | doi = 10.1002/ejoc.200700427 }}</ref> and total syntheses of both (–)-cocaine and (–)-ferruginine via shared intermediates.<ref>{{cite journal | vauthors = Cheng G, Wang X, Zhu R, Shao C, Xu J, Hu Y | title = Total synthesis of (-)-cocaine and (-)-ferruginine | journal = The Journal of Organic Chemistry | volume = 76 | issue = 8 | pages = 2694–2700 | date = April 2011 | pmid = 21391709 | doi = 10.1021/jo200069m }}</ref> Together, these diverse approaches highlight ferruginine as a longstanding challenge in synthetic organic chemistry, with catalytic systems ranging from Rh2(oct)4 to Wilkinson's catalyst finding application in key synthetic steps.<ref>{{cite book | vauthors = Doyle MP, Davies H, Manning JR | chapter = Dirhodium(II) Tetraoctanoate | title = Encyclopedia of Reagents for Organic Synthesis | article-number = rd462.pub2 | date = 15 April 2006 | doi = 10.1002/047084289X.rd462.pub2 | publisher = John Wiley & Sons | isbn = 0-471-93623-5 | chapter-url = https://onlinelibrary.wiley.com/doi/10.1002/047084289X.rd462.pub2 }}</ref>

The '''unnatural''' enantiomer of ferruginine (see picture) was made from natural cocaine.<ref name = "Katoh_2002" /><ref name=Bick>{{cite journal | vauthors = Bick I, Gillard J, Leow H | journal=Australian Journal of Chemistry | title=Alkaloids of Darlingia ferruginea | volume=32 | issue=11 | pages=2537 | date= 1979 | doi=10.1071/CH9792537}}</ref> In the cited reference (<ref name = "Katoh_2002" />) it says (−)-ferruginine (cocaine isomer) was found to be an agonist for the nicotine acetylcholine receptor.<ref>{{cite book | vauthors = Herken H, Aktories K, Hucho F | chapter = Selective Neurotoxicity | veditors = Swanson KL, Albuquerque EX | title = Handbook of experimental pharmacology | volume = 102 | publisher = Springer | date = 1992 | page = 620–621 }}</ref><ref name="Gündisch_2001"/><ref name="Gündisch_2002">{{cite journal | vauthors = Gündisch D, Kämpchen T, Schwarz S, Seitz G, Siegl J, Wegge T | title = Syntheses and evaluation of pyridazine and pyrimidine containing bioisosteres of (+/-)-pyrido[3.4-b]homotropane and pyrido-[3.4-b]tropane as novel nAChR ligands | journal = Bioorganic & Medicinal Chemistry | volume = 10 | issue = 1 | pages = 1–9 | date = January 2002 | pmid = 11738601 | doi = 10.1016/S0968-0896(01)00258-9 }}</ref> However there appears to be an underlying discrepancy in that according to John W. Daly, the (+)-enantiomer was 7600nM and the value for the (−)-enantiomer was 120nM.<ref>{{cite journal | vauthors= Daly JW | journal=Cellular and Molecular Neurobiology | title=Nicotinic Agonists, Antagonists, and Modulators From Natural Sources | volume=25 | issue=3–4 | pages=513–552 | date= June 2005 | doi=10.1007/s10571-005-3968-4| pmc=11529529 }}</ref>

==See also== *Ferrugine<ref name=Bick/> *Darlingine<ref name=Bick/> *Anatoxin A {{cs1 config|name-list-style=vanc|display-authors=6}} *The WF-23 analog is called [https://pubchem.ncbi.nlm.nih.gov/compound/44458708 PC44458708]<ref>{{cite journal | vauthors = Davies HM, Saikali E, Huby NJ, Gilliatt VJ, Matasi JJ, Sexton T, Childers SR | title = Synthesis of 2 beta-acyl-3 beta-aryl-8-azabicyclo[3.2.1]octanes and their binding affinities at dopamine and serotonin transport sites in rat striatum and frontal cortex | journal = Journal of Medicinal Chemistry | volume = 37 | issue = 9 | pages = 1262–1268 | date = April 1994 | pmid = 8176704 | doi = 10.1021/jm00035a005 }}</ref><ref>{{cite journal | vauthors = Davies HM, Gilliatt V, Kuhn LA, Saikali E, Ren P, Hammond PS, Sexton T, Childers SR | title = Synthesis of 2beta-acyl-3beta-(substituted naphthyl)-8-azabicyclo[3.2.1]octanes and their binding affinities at dopamine and serotonin transport sites | journal = Journal of Medicinal Chemistry | volume = 44 | issue = 10 | pages = 1509–1515 | date = May 2001 | pmid = 11334561 | doi = 10.1021/jm000363+ }}</ref>

== References == {{reflist}} {{Alkaloids}} Category:Tropane alkaloids Category:Ketones Category:Alkaloids