Chemistry:Naxagolide

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Naxagolide (INN), also known as PHNO, dopazinol, L-647339, and MK-458 among other synonyms, is a dopamine receptor agonist which was developed for the treatment of Parkinson's disease but was never marketed.[1][2][3][4] A radiolabeled form has been used for brain imaging.[5][3] The drug was developed for use both orally and transdermally.[4][6]

It acts as a potent dopamine D2 and D3 receptor agonist.[6][7] Naxagolide was described in the 1990s as the most potent dopamine D2 receptor agonist that had been used.[8][9] It shows about 50-fold selectivity for the dopamine D3 receptor over the dopamine D2 receptor (Ki = 0.16 nM vs. 8.5 nM).[7] The drug is a naphthoxazine derivative.[6] It is structurally similar to ergolines such as pergolide and cabergoline but is a non-ergoline itself.[10][9]

Naxagolide was first described in 1984 and was under development by Merck & Co in the 1980s and 1990s.[3][4] It was developed for treatment of Parkinson's disease and reached phase 2 clinical trials for this indication.[3] The drug was discontinued due to inadequate effectiveness and/or due to toxicity.[6][8]

See also

References

  1. ↑ The Dictionary of Drugs: Chemical Data: Chemical Data, Structures and Bibliographies. Springer US. 2014. p. 856. ISBN 978-1-4757-2085-3. https://books.google.com/books?id=0vXTBwAAQBAJ&pg=PA856. Retrieved 23 February 2025. 
  2. ↑ Concise Dictionary of Pharmacological Agents: Properties and Synonyms. Springer Netherlands. 2012. p. 190. ISBN 978-94-011-4439-1. https://books.google.com/books?id=tsjrCAAAQBAJ&pg=PA190. Retrieved 23 February 2025. 
  3. ↑ 3.0 3.1 3.2 3.3 "Synthesis of Carbon-11 Labeled (+)-4-Propyl-3,4,4a,5,6,10b-Hexahydro-2 H -Naphtho[1,2- B ][1,4]Oxazin-9-Ol ([ 11 C]-(+)-PHNO)". Radiochemical Syntheses. Wiley. 22 May 2015. pp. 81–92. doi:10.1002/9781118834114.ch9. ISBN 978-1-118-23784-7. 
  4. ↑ 4.0 4.1 4.2 "Naxagolide". 24 October 2021. https://adisinsight.springer.com/drugs/800002657. 
  5. ↑ "Schizophrenia and dopamine receptors". European Neuropsychopharmacology 23 (9): 999–1009. September 2013. doi:10.1016/j.euroneuro.2013.06.005. PMID 23860356. 
  6. ↑ 6.0 6.1 6.2 6.3 "Transdermal Drug Delivery in Parkinson's Disease". Aging Health 3 (4): 471–482. 2007. doi:10.2217/1745509X.3.4.471. ISSN 1745-509X. 
  7. ↑ 7.0 7.1 "Current state of agonist radioligands for imaging of brain dopamine D2/D3 receptors in vivo with positron emission tomography". Current Topics in Medicinal Chemistry 10 (15): 1477–1498. 2010. doi:10.2174/156802610793176837. PMID 20583987. 
  8. ↑ 8.0 8.1 "Treatment of Parkinson's disease. Advances in the pharmacological therapy". European Neurology 36 (6): 396–399. 1996. doi:10.1159/000117303. PMID 8954312. "PHNO (naxagolide, MK 458) [21], the most potent D2 agonist ever used, has been withdrawn because of animal toxicity, and this is also the case for mesulergin (CU 32 085), a D1 and D2 agonist.". 
  9. ↑ 9.0 9.1 Parkinsons's Disease: The Treatment Options. Taylor & Francis. 1999. p. 170. ISBN 978-1-85317-379-0. https://books.google.com/books?id=wOQf3XcExF8C&pg=PA170. Retrieved 23 February 2025. "Two non-ergot dopaminergic agonists were developed for the potential of transdermal administration. (+)4—Propyl-9-hydroxynaphthoxazine (PHNO; also known as MK-458 or naxagolide), perhaps the most potent dopaminergic compound, is readily absorbed through the skin. Although administration of PHNO in an oral sustained-release form showed antiparkinsonian effectiveness,147 this drug was discontinued from further development before the transdermal delivery route could be tested in human subjects." 
  10. ↑ "Naxagolide". https://pubchem.ncbi.nlm.nih.gov/compound/57533. 



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