Naxagolide

Naxagolide
Clinical data
Other names	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
Routes of; administration	Oral; Transdermal
Drug class	Dopamine D2 and D3 receptor agonist; Antiparkinsonian agent
Identifiers
	IUPAC name (4aR,10bR)-4-propyl-2,3,4a,5,6,10b-hexahydrobenzo[h][1,4]benzoxazin-9-ol;
CAS Number	88058-88-2;
PubChem CID	57533;
ChemSpider	51863;
UNII	22Z7E0X6OF;
ChEBI	CHEBI:177372;
ChEMBL	ChEMBL69271;
CompTox Dashboard (EPA)	DTXSID60236782 ;
Chemical and physical data
Formula	C15H21NO2
Molar mass	247.338 g·mol−1
3D model (JSmol)	Interactive image;
	SMILES CCCN1CCO[C@H]2[C@H]1CCC3=C2C=C(C=C3)O;
	InChI 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 (INNTooltip 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 (K_i = 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]

References

^ 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.
^ 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.
^ ^a ^b ^c ^d 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.
^ ^a ^b ^c "Naxagolide". AdisInsight. 24 October 2021. Retrieved 23 February 2025.
^ Seeman P (September 2013). "Schizophrenia and dopamine receptors". European Neuropsychopharmacology. 23 (9): 999–1009. doi:10.1016/j.euroneuro.2013.06.005. PMID 23860356.
^ ^a ^b ^c ^d 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.
^ ^a ^b 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.
^ ^a ^b 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.
^ ^a ^b 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.
^ "Naxagolide". PubChem. Retrieved 23 February 2025.

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[Elks2014-1] 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.

[MortonHall2012-2] 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.

[PlissonRamada-MagalhaesPasschier2015-3] 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.

[AdisInsight-4] "Naxagolide". AdisInsight. 24 October 2021. Retrieved 23 February 2025.

[Seeman2013-5] Seeman P (September 2013). "Schizophrenia and dopamine receptors". European Neuropsychopharmacology. 23 (9): 999–1009. doi:10.1016/j.euroneuro.2013.06.005. PMID 23860356.

[Pfeiffer2007-6] 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.

[FinnemaBang-AndersonWikström2010-7] 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.

[KuntzerGhikaPollak1996-8] 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.

[LewittOertel1999-9] 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.

[PubChem-10] "Naxagolide". PubChem. Retrieved 23 February 2025.

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Naxagolide

See also

References

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