Naxagolide

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| image = Naxagolide.svg

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| routes_of_administration = Oral; Transdermal

| class = Dopamine D₂ and D₃ receptor agonist; Antiparkinsonian agent

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| CAS_number = 88058-88-2

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| PubChem = 57533

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| ChemSpiderID = 51863

| UNII = 22Z7E0X6OF

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| ChEBI = 177372

| ChEMBL = 69271

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| synonyms = Dopazinol; Nazagolide; PHNO; (+)-PHNO; (+)-4-Propyl-9-hydroxynaphthoxazine; 4-Propyl-9-hydroxy-1,2,3,4a,5,6-hexahydronaphthoxazine; L-647339; L647339; MK-458; MK458

| IUPAC_name = (4aR,10bR)-4-propyl-2,3,4a,5,6,10b-hexahydrobenzo[h][1,4]benzoxazin-9-ol

| C=15 | H=21 | N=1 | O=2

| SMILES = CCCN1CCO[C@H]2[C@H]1CCC3=C2C=C(C=C3)O

| StdInChI = 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

| StdInChIKey = JCSREICEMHWFAY-HUUCEWRRSA-N

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Naxagolide ({{Abbrlink|INN|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.{{cite book | vauthors = Elks J | title=The Dictionary of Drugs: Chemical Data: Chemical Data, Structures and Bibliographies | publisher=Springer US | year=2014 | isbn=978-1-4757-2085-3 | url=https://books.google.com/books?id=0vXTBwAAQBAJ&pg=PA856 | access-date=23 February 2025 | page=856}}{{cite book | vauthors = Morton I, Hall J | title=Concise Dictionary of Pharmacological Agents: Properties and Synonyms | publisher=Springer Netherlands | year=2012 | isbn=978-94-011-4439-1 | url=https://books.google.com/books?id=tsjrCAAAQBAJ&pg=PA190 | access-date=23 February 2025 | page=190}}{{cite book | vauthors = Plisson C, Ramada-Magalhaes J, Passchier J | title=Radiochemical Syntheses | chapter=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) | publisher=Wiley | date=22 May 2015 | isbn=978-1-118-23784-7 | doi=10.1002/9781118834114.ch9 | pages=81–92}} A radiolabeled form has been used for brain imaging.{{cite journal | vauthors = Seeman P | title = Schizophrenia and dopamine receptors | journal = European Neuropsychopharmacology | volume = 23 | issue = 9 | pages = 999–1009 | date = September 2013 | pmid = 23860356 | doi = 10.1016/j.euroneuro.2013.06.005 }} The drug was developed for use both orally and transdermally.

It acts as a potent dopamine D₂ and D₃ receptor agonist.{{cite journal | vauthors = Finnema SJ, Bang-Andersen B, Wikström HV, Halldin C | title = Current state of agonist radioligands for imaging of brain dopamine D2/D3 receptors in vivo with positron emission tomography | journal = Current Topics in Medicinal Chemistry | volume = 10 | issue = 15 | pages = 1477–1498 | date = 2010 | pmid = 20583987 | doi = 10.2174/156802610793176837 }} Naxagolide was described in the 1990s as the most potent dopamine D₂ receptor agonist that had been used.{{cite book | vauthors = Lewitt P, Oertel W | title=Parkinsons's Disease: The Treatment Options | publisher=Taylor & Francis | year=1999 | isbn=978-1-85317-379-0 | url=https://books.google.com/books?id=wOQf3XcExF8C&pg=PA170 | access-date=23 February 2025 | page=170 | quote=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.}} It shows about 50-fold selectivity for the dopamine D₃ receptor over the dopamine D₂ receptor (K_i = 0.16{{nbsp}}nM vs. 8.5{{nbsp}}nM). The drug is a naphthoxazine derivative. It is structurally similar to ergolines such as pergolide and cabergoline but is a non-ergoline itself.{{cite web | title=Naxagolide | website=PubChem | url=https://pubchem.ncbi.nlm.nih.gov/compound/57533 | access-date=23 February 2025}}

Naxagolide was first described in 1984 and was under development by Merck & Co in the 1980s and 1990s.{{cite web | title=Naxagolide | website=AdisInsight | date=24 October 2021 | url=https://adisinsight.springer.com/drugs/800002657 | access-date=23 February 2025}} It was developed for treatment of Parkinson's disease and reached phase 2 clinical trials for this indication. The drug was discontinued due to inadequate effectiveness and/or due to toxicity.{{cite journal | vauthors = Pfeiffer RF | title=Transdermal Drug Delivery in Parkinson's Disease | journal=Aging Health | volume=3 | issue=4 | date=2007 | issn=1745-509X | doi=10.2217/1745509X.3.4.471 | pages=471–482}}{{cite journal | vauthors = Kuntzer T, Ghika J, Pollak P, Benabid AL, Limousin P, Krack P, Zurn AD, Tseng J, Aebischer P | title = Treatment of Parkinson's disease. Advances in the pharmacological therapy | journal = European Neurology | volume = 36 | issue = 6 | pages = 396–399 | date = 1996 | pmid = 8954312 | doi = 10.1159/000117303 | quote = 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. }}