Naxagolide

Last updated

Naxagolide
Naxagolide.svg
Clinical data
Other namesDopazinol; Nazagolide; PHNO; (+)-PHNO; (+)-4-Propyl-9-hydroxynaphthoxazine; 4-Propyl-9-hydroxy-1,2,3,4a,5,6-hexahydronaphthoxazine; L-647339; L647339; MK-458; MK458
Routes of
administration 		Oral; Transdermal
Drug class Dopamine D2 and D3 receptor agonist; Antiparkinsonian agent
Identifiers
  • (4aR,10bR)-4-propyl-2,3,4a,5,6,10b-hexahydrobenzo[h][1,4]benzoxazin-9-ol
CAS Number
PubChem CID
ChemSpider
UNII
ChEBI
ChEMBL
Chemical and physical data
Formula C15H21NO2
Molar mass 247.338 g·mol−1
3D model (JSmol)
  • CCCN1CCO[C@H]2[C@H]1CCC3=C2C=C(C=C3)O
  • InChI=1S/C15H21NO2/c1-2-7-16-8-9-18-15-13-10-12(17)5-3-11(13)4-6-14(15)16/h3,5,10,14-15,17H,2,4,6-9H2,1H3/t14-,15-/m1/s1
  • Key:JCSREICEMHWFAY-HUUCEWRRSA-N

Naxagolide (INN Tooltip International Nonproprietary Name), 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. ↑ Elks J (2014). The Dictionary of Drugs: Chemical Data: Chemical Data, Structures and Bibliographies. Springer US. p. 856. ISBN   978-1-4757-2085-3 . Retrieved 23 February 2025.
  2. ↑ Morton I, Hall J (2012). Concise Dictionary of Pharmacological Agents: Properties and Synonyms. Springer Netherlands. p. 190. ISBN   978-94-011-4439-1 . Retrieved 23 February 2025.
  3. 1 2 3 4 Plisson C, Ramada-Magalhaes J, Passchier J (22 May 2015). "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. pp. 81–92. doi:10.1002/9781118834114.ch9. ISBN   978-1-118-23784-7.
  4. 1 2 3 "Naxagolide". AdisInsight. 24 October 2021. Retrieved 23 February 2025.
  5. ↑ Seeman P (September 2013). "Schizophrenia and dopamine receptors". European Neuropsychopharmacology. 23 (9): 999–1009. doi:10.1016/j.euroneuro.2013.06.005. PMID   23860356.
  6. 1 2 3 4 Pfeiffer RF (2007). "Transdermal Drug Delivery in Parkinson's Disease". Aging Health. 3 (4): 471–482. doi:10.2217/1745509X.3.4.471. ISSN   1745-509X.
  7. 1 2 Finnema SJ, Bang-Andersen B, Wikström HV, Halldin C (2010). "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. doi:10.2174/156802610793176837. PMID   20583987.
  8. 1 2 Kuntzer T, Ghika J, Pollak P, Benabid AL, Limousin P, Krack P, et al. (1996). "Treatment of Parkinson's disease. Advances in the pharmacological therapy". European Neurology. 36 (6): 396–399. 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. 1 2 Lewitt P, Oertel W (1999). Parkinsons's Disease: The Treatment Options. Taylor & Francis. p. 170. ISBN   978-1-85317-379-0 . 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". PubChem. Retrieved 23 February 2025.
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