Rimantadine

Rimantadine inhibits influenza activity by binding to amino acids in the M2 transmembrane channel and blocking proton transport across the M2 channel.{{cite journal | vauthors = Vorobjev YN | title = An effective molecular blocker of ion channel of M2 protein as anti-influenza A drug. | journal = Journal of Biomolecular Structure and Dynamics | date = April 2020 | volume = 39 | issue = 7 | pages = 2352–2363 | doi = 10.1080/07391102.2020.1747550 |issn=0739-1102 | pmid = 32212957 | s2cid = 214681984 }} Rimantadine is believed to inhibit influenza's viral replication, possibly by preventing the uncoating of the virus's protective shells, which are the envelope and capsid. The M2 channel is known to be responsible for viral replication in the influenza virus. Genetic studies suggest that the virus M2 protein, an ion channel specified by virion M2 gene, plays an important role in the susceptibility of influenza A virus to inhibition by rimantadine.{{cn|date=August 2022}}

Rimantadine is bound inside the pore to amantadine specific amino acid binding sites with hydrogen binding and van der Waals interactions.{{cite journal | vauthors = Drakopoulos A, Tzitzoglaki C, Ma C, Freudenberger K, Hoffmann A, Hu Y, Gauglitz G, Schmidtke M, Wang J, Kolocouris A | display-authors = 6 | title = Affinity of Rimantadine Enantiomers against Influenza A/M2 Protein Revisited | journal = ACS Medicinal Chemistry Letters | volume = 8 | issue = 2 | pages = 145–150 | date = February 2017 | pmid = 28217261 | pmc = 5312807 | doi = 10.1021/acsmedchemlett.6b00311 }} The ammonium group (with neighboring water molecules) is positioned towards the C terminus with the amantadane group is positioned towards the N-terminus when bound inside the M2 pore.{{cn|date=January 2023}}

File:Rimantadine S31N Mutation Binding.png

Resistance to rimantadine can occur as a result of amino acid substitutions at certain locations in the transmembrane region of M2. This prevents binding of the antiviral to the channel.{{cite journal | vauthors = Jing X, Ma C, Ohigashi Y, Oliveira FA, Jardetzky TS, Pinto LH, Lamb RA | title = Functional studies indicate amantadine binds to the pore of the influenza A virus M2 proton-selective ion channel | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 105 | issue = 31 | pages = 10967–72 | date = August 2008 | pmid = 18669647 | pmc = 2492755 | doi = 10.1073/pnas.0804958105 | bibcode = 2008PNAS..10510967J | doi-access = free }}

The mutation S31N binding site with rimantadine is shown in the image to the left. It shows rimantadine binding into lumenal (top) or peripheral (bottom) binding sites with influenza M2 channel Serine 31 (gold) or Asparagine 31 (blue).{{cn|date=January 2023}}

Rimantadine, when sold as flumadine, is present as a racemic mixture; the R and S states are both present in the drug. Solid state NMR studies have shown that the R enantiomer has a stronger binding affinity to the M2 channel pore than the S-enantiomer of rimantadine.{{cite journal | vauthors = Wright AK, Batsomboon P, Dai J, Hung I, Zhou HX, Dudley GB, Cross TA | title = Differential Binding of Rimantadine Enantiomers to Influenza A M2 Proton Channel | journal = Journal of the American Chemical Society | volume = 138 | issue = 5 | pages = 1506–9 | date = February 2016 | pmid = 26804976 | doi = 10.1021/jacs.5b13129 | pmc = 9328162 | bibcode = 2016JAChS.138.1506W }} Antiviral assay and electrophysiology studies show that there is no significant difference between the R and S enantiomers in binding affinity to amino acids in the M2 channel.{{cite journal | vauthors = Drakopoulos A, Tzitzoglaki C, Ma C, Freudenberger K, Hoffmann A, Hu Y, Gauglitz G, Schmidtke M, Wang J, Kolocouris A | display-authors = 6 | title = Affinity of Rimantadine Enantiomers against Influenza A/M2 Protein Revisited | journal = ACS Medicinal Chemistry Letters | volume = 8 | issue = 2 | pages = 145–150 | date = February 2017 | pmid = 28217261 | pmc = 5312807 | doi = 10.1021/acsmedchemlett.6b00311 }} Since the enantiomers have similar binding affinity, they also have similar ability to block the channel pore and work as an effective antiviral.{{cn|date=January 2023}}

Rimantadine enantiomers R and S are pictured interacting with the M2 pore below to the right. This image shows that there is not a significant modeled difference between the R and S enantiomers.{{cn|date=February 2025}}

Rimantadine, like its antiviral cousin amantadine, possesses antiparkinsonian activity and can be used in the treatment of Parkinson's disease.{{cite journal | vauthors = Evidente VG, Adler CH, Caviness JN, Gwinn-Hardy K | title = A pilot study on the motor effects of rimantadine in Parkinson's disease | journal = Clin Neuropharmacol | volume = 22 | issue = 1 | pages = 30–32 | date = 1999 | pmid = 10047931 | doi = 10.1097/00002826-199901000-00006 | url = }}{{cite journal | vauthors = Singer C, Papapetropoulos S, Gonzalez MA, Roberts EL, Lieberman A | title = Rimantadine in Parkinson's disease patients experiencing peripheral adverse effects from amantadine: report of a case series | journal = Mov Disord | volume = 20 | issue = 7 | pages = 873–877 | date = July 2005 | pmid = 15809995 | doi = 10.1002/mds.20471 | url = }} However, in general, neither rimantadine nor amantadine is a preferred agent for this therapy and would be reserved for cases of the disease that are less responsive to front-line treatments.{{cn|date=January 2023}}

Rimantadine is shown to be effective against other RNA-containing viruses. It can treat arboviruses like Saint Louis encephalitis and Sindbis. Other viruses that can be treated with Rimantadine include respiratory synctial{{typo help inline|reason=similar to syncytial|date=October 2022}} and parainfluenza viruses.{{cite journal | vauthors = Zlydnikov DM, Kubar OI, Kovaleva TP, Kamforin LE | title = Study of rimantadine in the USSR: a review of the literature | journal = Reviews of Infectious Diseases | volume = 3 | issue = 3 | pages = 408–21 | date = 1981-05-01 | pmid = 7025146 | doi = 10.1093/clinids/3.3.408 }} Rimantadine has also been shown to treat chronic hepatitis C.{{cite journal | vauthors = Younossi ZM, Perrillo RP | title = The roles of amantadine, rimantadine, ursodeoxycholic acid, and NSAIDs, alone or in combination with alpha interferons, in the treatment of chronic hepatitis C | journal = Seminars in Liver Disease | volume = 19 | pages = 95–102 | date = 1999 | issue = Suppl 1 | pmid = 10349697 }}

Rimantadine can produce gastrointestinal and central nervous system adverse effects. Approximately 6% of patients (compared to 4% of patients taking a placebo) reported side-effects at a dosage of 200 mg/d.{{cite web |url=https://www.cdc.gov/flu/professionals/treatment/side-effects.htm |title=CDC - Influenza (Flu) | Antivirals: Side-Effects | REMOVED! |access-date=2008-11-05}}

Common side effects include:{{cn|date=February 2025}}

• Nausea
• Upset stomach
• Nervousness
• Tiredness
• Lightheadedness
• Trouble sleeping (insomnia)
• Difficulty concentrating
• Confusion

Rimantadine shows fewer CNS symptoms than its sister drug amantadine.{{cite journal | vauthors = Zimmerman RK | title = Rationing of influenza vaccine during a pandemic: ethical analyses | journal = Vaccine | volume = 25 | issue = 11 | pages = 2019–26 | date = March 2007 | pmid = 17258359 | doi = 10.1016/j.vaccine.2006.11.045 }}

• Taking paracetamol (acetaminophen, Tylenol) or acetylsalicylic acid (aspirin) while taking rimantadine is known to reduce the body's uptake of rimantadine by approximately 12%.{{cite web|url=https://www.fda.gov/cder/drug/antivirals/influenza/flumadine.htm |title=fda.gov |website=Food and Drug Administration |access-date=2008-11-05 |url-status=dead |archive-url=https://web.archive.org/web/20050630080607/https://www.fda.gov/cder/drug/antivirals/influenza/flumadine.htm |archive-date=June 30, 2005 }}
• Cimetidine also affects the body's uptake of rimantadine.{{cn|date=January 2023}}
• Taking anticholinergic drugs with amantadine may increase underlying seizure disorders and aggravate congestive heart failure.{{cite journal | vauthors = Zimmerman RK | title = Rationing of influenza vaccine during a pandemic: ethical analyses | journal = Vaccine | volume = 25 | issue = 11 | pages = 2019–26 | date = March 2007 | pmid = 17258359 | doi = 10.1016/j.vaccine.2006.11.045 }}

The related drugs memantine and to a much lesser extent amantadine are known to act as NMDA receptor antagonists.{{cite journal | vauthors = Danysz W, Parsons CG, Kornhuber J, Schmidt WJ, Quack G | title = Aminoadamantanes as NMDA receptor antagonists and antiparkinsonian agents--preclinical studies | journal = Neurosci Biobehav Rev | volume = 21 | issue = 4 | pages = 455–468 | date = July 1997 | pmid = 9195603 | doi = 10.1016/s0149-7634(96)00037-1 | url = }}{{cite journal | vauthors = Danysz W, Dekundy A, Scheschonka A, Riederer P | title = Amantadine: reappraisal of the timeless diamond-target updates and novel therapeutic potentials | journal = J Neural Transm (Vienna) | volume = 128 | issue = 2 | pages = 127–169 | date = February 2021 | pmid = 33624170 | pmc = 7901515 | doi = 10.1007/s00702-021-02306-2 | url = }} The affinity of rimantadine for the NMDA receptor does not seem to have been reported.{{cite web | last=Liu | first=Tiqing | title=BindingDB BDBM50216627 (alpha-methyl-1-adamantyl)methylamine::1-Adamantan-1-yl-ethylamine::CHEMBL959::RIMANTADINE::US11241393, Rimantadine::rimantadin::rimantidin | website=BindingDB | url=https://www.bindingdb.org/rwd/bind/chemsearch/marvin/MolStructure.jsp?monomerid=50216627 | access-date=13 September 2024}}{{cite web | title=PDSP Database | website=UNC | url=https://pdsp.unc.edu/databases/pdsp.php?receptorDD=&receptor=&speciesDD=&species=&sourcesDD=&source=&hotLigandDD=&hotLigand=&testLigandDD=&testFreeRadio=testFreeRadio&testLigand=Rimantadine&referenceDD=&reference=&KiGreater=&KiLess=&kiAllRadio=all&doQuery=Submit+Query | language=zu | access-date=13 September 2024}}{{cite web | title=rimantadine (NMDA OR NMDAR OR NMDARs OR "N-methyl-D-aspartate") | website=PubMed | url=https://pubmed.ncbi.nlm.nih.gov/?term=rimantadine+%28NMDA+OR+NMDAR+OR+NMDARs+OR+%22N-methyl-D-aspartate%22%29&sort=date&sort_order=asc&size=200 | access-date=13 September 2024}} Analogues of rimantadine are known to act as NMDA receptor antagonists.{{cite journal | vauthors = Camps P, Duque MD, Vázquez S, Naesens L, De Clercq E, Sureda FX, López-Querol M, Camins A, Pallàs M, Prathalingam SR, Kelly JM, Romero V, Ivorra D, Cortés D | title = Synthesis and pharmacological evaluation of several ring-contracted amantadine analogs | journal = Bioorg Med Chem | volume = 16 | issue = 23 | pages = 9925–9936 | date = December 2008 | pmid = 18954995 | pmc = 7125889 | doi = 10.1016/j.bmc.2008.10.028 | url = }}

File:Rimantadine synthesis 1.PNG

1-carboxyadamatanones are reduced with sodium borohydride to create racemic hydroxy acid. Excess methyllithium is then added to create methyl ketones which when reduced with lithium aluminum hydride gives the amine group.{{cite journal | vauthors = Manchand PS, Cerruti RL, Martin JA, Hill CH, Merrett JH, Keech E, Belshe RB, Connell EV, Sim IS | display-authors = 6 | title = Synthesis and antiviral activity of metabolites of rimantadine | journal = Journal of Medicinal Chemistry | volume = 33 | issue = 7 | pages = 1992–5 | date = July 1990 | pmid = 2362279 | doi = 10.1021/jm00169a029 }}

The synthesis pictured to the left is a synthesis of rimantadine as synthesized in Europe.{{cn|date=February 2025}}

Rimantadine was discovered in 1963[http://www.freepatentsonline.com/3352912.pdf US patent 3352912 to W. W. Prichard][http://www.freepatentsonline.com/4551552.html United States Patent № 4551552: Process for preparing rimantadine]: Rimantadine and related compounds useful as antivirals were first described by Prichard in U.S. Pat. Nos. 3,352,912 and 3,592,934. Both patents describe the preparation of rimantadine from the corresponding ketone oxime by reduction with lithium aluminum hydride. and patented in 1965 in the US by William W. Prichard in Du Pont & Co., Wilmington, Delaware (patent on new chemical compound {{US patent|3352912}}, 1965 and on the first method of synthesis {{US patent|3592934}}, 1967).[http://www.freepatentsonline.com/4551552.html United States Patent № 4551552: Process for preparing rimantadine]{{cite journal | vauthors = Zlydnikov DM, Kubar OI, Kovaleva TP, Kamforin LE | title = Study of rimantadine in the USSR: a review of the literature | journal = Reviews of Infectious Diseases | volume = 3 | issue = 3 | pages = 408–21 | year = 1981 | pmid = 7025146 | doi = 10.1093/clinids/3.3.408 }} Prichard's methods of synthesis of rimantadine from the corresponding ketone oxime were based on its reduction with lithium aluminum hydride.{{cn|date=January 2023}}

• Adapromine
• Bromantane
• Memantine
• Tromantadine

{{Reflist|2}}

• [https://www.fda.gov/bbs/topics/ANSWERS/ANS00530.html U.S. FDA press release announcing rimantadine's approval]
• [https://www.fda.gov/cder/drug/antivirals/influenza/flumadine.htm U.S. Center for Drug Evaluation and Research rimantadine description]
• [https://www.nlm.nih.gov/medlineplus/druginfo/medmaster/a698029.html U.S. NIH rimantadine description]
• [https://www.cdc.gov/flu/professionals/treatment/index.htm U.S. CDC flu anti-viral treatment information]

{{RNA antivirals}}

{{Influenza}}

{{Antiparkinson}}

{{Navboxes

| title = Pharmacodynamics

| titlestyle = background:#ccccff

| list1 =

{{Dopamine receptor modulators}}

}}

Category:Adamantanes

Category:Amines

Category:Anti-influenza agents

Category:Drugs with unknown mechanisms of action

Category:Proton channel blockers

Category:Suspected embryotoxicants

Category:Suspected teratogens