Preladenant

Preladenant
Clinical data
Other names	SCH-420814
Routes of; administration	Oral
ATC code	none;
Legal status
Legal status	Investigational;
Identifiers
	IUPAC name 2-(2-Furanyl)-7-[2-[4-[4-(2-methoxyethoxy)phenyl]-1-piperazinyl]ethyl]7H-pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidine-5-amine;
CAS Number	377727-87-2 ;
PubChem CID	10117987;
IUPHAR/BPS	5614;
ChemSpider	8293510 ;
UNII	950O97NUPO;
KEGG	D09717;
CompTox Dashboard (EPA)	DTXSID90191219 ;
ECHA InfoCard	100.210.813
Chemical and physical data
Formula	C25H29N9O3
Molar mass	503.567 g·mol−1
3D model (JSmol)	Interactive image;
	SMILES COCCOc(cc4)ccc4N(CC3)CCN3CCn(c2nc1N)ncc2c(n5)n1nc5-c6occc6;
	InChI InChI=1S/C25H29N9O3/c1-35-15-16-36-19-6-4-18(5-7-19)32-11-8-31(9-12-32)10-13-33-23-20(17-27-33)24-28-22(21-3-2-14-37-21)30-34(24)25(26)29-23/h2-7,14,17H,8-13,15-16H2,1H3,(H2,26,29) ; Key:DTYWJKSSUANMHD-UHFFFAOYSA-N ;
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Preladenant (developmental code name SCH-420814) is a drug that was developed by Schering-Plough which acted as a potent and selective antagonist of the adenosine A_2A receptor.^[1] It was being researched as a potential treatment for Parkinson's disease.^[2] Positive results were reported in Phase II clinical trials in humans,^[3] but it did not prove itself to be more effective than a placebo during Phase III trials, and so was discontinued in May 2013.^[4]

The drug has very high affinity for the A_2A receptor (<1 nM) and shows more than 1,000-fold selectivity for the A_2A receptor over the adenosine A₁ receptor.^[1]

Preladenant shows pro-motivational effects in animals and reverses tetrabenazine-induced motivational deficits.^[1]^[5] Other A_2A receptor antagonists, including MSX-3, MSX-4, and istradefylline, have also shown such effects.^[1]^[5] These agents may be useful in the treatment of motivational disorders in humans.^[1]^[5] Accordingly, istradefylline has been reported to reduce apathy, anhedonia, fatigue, and depression in people with Parkinson's disease.^[6]^[1]

References

^ ^a ^b ^c ^d ^e ^f Salamone JD, Correa M, Ferrigno S, Yang JH, Rotolo RA, Presby RE (October 2018). "The Psychopharmacology of Effort-Related Decision Making: Dopamine, Adenosine, and Insights into the Neurochemistry of Motivation". Pharmacol Rev. 70 (4): 747–762. doi:10.1124/pr.117.015107. PMC 6169368. PMID 30209181.
^ Hodgson RA, Bertorelli R, Varty GB, Lachowicz JE, Forlani A, Fredduzzi S, et al. (July 2009). "Characterization of the potent and highly selective A2A receptor antagonists preladenant and SCH 412348 [7-[2-[4-2,4-difluorophenyl]-1-piperazinyl]ethyl]-2-(2-furanyl)-7H-pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidin-5-amine] in rodent models of movement disorders and depression". The Journal of Pharmacology and Experimental Therapeutics. 330 (1): 294–303. doi:10.1124/jpet.108.149617. PMID 19332567. S2CID 22033475.
^ Hauser RA, Cantillon M, Pourcher E, Micheli F, Mok V, Onofrj M, et al. (March 2011). "Preladenant in patients with Parkinson's disease and motor fluctuations: a phase 2, double-blind, randomised trial". The Lancet. Neurology. 10 (3): 221–229. doi:10.1016/S1474-4422(11)70012-6. PMID 21315654. S2CID 39226234.
^ "Merck ends development of Parkinson's disease drug". The Big Story. Associated Press. 23 May 2013. Archived from the original on 2013-06-16. Retrieved 2013-05-23.
^ ^a ^b ^c Treadway MT, Salamone JD (2022). "Vigor, Effort-Related Aspects of Motivation and Anhedonia". Curr Top Behav Neurosci. 58: 325–353. doi:10.1007/7854_2022_355. PMID 35505057. Adenosine A2A receptor antagonists have been studied for their potential antiparkinsonian effects (Ferré 1997; Morelli and Pinna 2002; Correa et al. 2004), and istradefylline (Nourianz) has been approved for use in several countries. Particularly relevant for the present review, drugs that act on adenosine A2A receptors induce substantial effects on instrumental behavior and effort-related choice. [...] Caffeine, theophylline, and several adenosine A2A receptor antagonists (MSX-3, MSX-4, Lu AA47070, istradefylline) can reverse the low-effort bias induced by systemically administered DA D2 antagonists (Farrar et al. 2007; Worden et al. 2009; Mott et al. 2009; Collins et al. 2012; Nunes et al. 2010; Santerre et al. 2012; Randall et al. 2012; Pardo et al. 2020), and MSX-3 and preladenant reverse the effects of TBZ (Nunes et al. 2013; Randall et al. 2014; Yohn et al. 2015a; Salamone et al. 2018). [...] Furthermore, A2A receptor knockout mice are resistant to the effort-related effects of haloperidol (Pardo et al. 2012). [...] Along with adenosine A2A antagonists such as istradefylline and preladenant (Nunes et al. 2013; Randall et al. 2014; Yohn et al. 2015a; Salamone et al. 2018), and D1 agonists (Yohn et al. 2015b), atypical DAT inhibitors offer promise as potential treatments for effort-related motivational symptoms.
^ Turner V, Husain M (2022). "Anhedonia in Neurodegenerative Diseases". Curr Top Behav Neurosci. 58: 255–277. doi:10.1007/7854_2022_352. PMID 35435648. Recently, PD patients have been treated with istradefylline, an adenosine A2A receptor antagonist used for treatment of motor symptoms. The drug was given to 14 PD patients for 12 weeks, measuring anhedonia, apathy and depression using the SHAPS, Apathy Scale and BDI. On istradefylline, SHAPS, Apathy Scale and BDI scores significantly reduced from baseline scores at 4-, 8- and 12-weeks, with mean SHAPS scores at week 12 about 50% reduced from baseline scores, indicating that istradefylline reduces anhedonia (Nagayama et al. 2019). As apathy and depression rates dropped as well as anhedonia, this trial also provided evidence for the overlapping relationship between the three symptoms. [...] Taken together, there is some evidence that dopamine agonists such as pramipexole and piribedil, or the adenosine A2A receptor antagonist istradefylline can improve anhedonia and apathy in PD.

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[SalamoneCorreaFerrigno2018-1] ^ ^a ^b ^c ^d ^e ^f Salamone JD, Correa M, Ferrigno S, Yang JH, Rotolo RA, Presby RE (October 2018). "The Psychopharmacology of Effort-Related Decision Making: Dopamine, Adenosine, and Insights into the Neurochemistry of Motivation". Pharmacol Rev. 70 (4): 747–762. doi:10.1124/pr.117.015107. PMC 6169368. PMID 30209181.

[pmid19332567-2] Hodgson RA, Bertorelli R, Varty GB, Lachowicz JE, Forlani A, Fredduzzi S, et al. (July 2009). "Characterization of the potent and highly selective A2A receptor antagonists preladenant and SCH 412348 [7-[2-[4-2,4-difluorophenyl]-1-piperazinyl]ethyl]-2-(2-furanyl)-7H-pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidin-5-amine] in rodent models of movement disorders and depression". The Journal of Pharmacology and Experimental Therapeutics. 330 (1): 294–303. doi:10.1124/jpet.108.149617. PMID 19332567. S2CID 22033475.

[3] Hauser RA, Cantillon M, Pourcher E, Micheli F, Mok V, Onofrj M, et al. (March 2011). "Preladenant in patients with Parkinson's disease and motor fluctuations: a phase 2, double-blind, randomised trial". The Lancet. Neurology. 10 (3): 221–229. doi:10.1016/S1474-4422(11)70012-6. PMID 21315654. S2CID 39226234.

[4] "Merck ends development of Parkinson's disease drug". The Big Story. Associated Press. 23 May 2013. Archived from the original on 2013-06-16. Retrieved 2013-05-23.

[TreadwaySalamone2022-5] Treadway MT, Salamone JD (2022). "Vigor, Effort-Related Aspects of Motivation and Anhedonia". Curr Top Behav Neurosci. 58: 325–353. doi:10.1007/7854_2022_355. PMID 35505057. Adenosine A2A receptor antagonists have been studied for their potential antiparkinsonian effects (Ferré 1997; Morelli and Pinna 2002; Correa et al. 2004), and istradefylline (Nourianz) has been approved for use in several countries. Particularly relevant for the present review, drugs that act on adenosine A2A receptors induce substantial effects on instrumental behavior and effort-related choice. [...] Caffeine, theophylline, and several adenosine A2A receptor antagonists (MSX-3, MSX-4, Lu AA47070, istradefylline) can reverse the low-effort bias induced by systemically administered DA D2 antagonists (Farrar et al. 2007; Worden et al. 2009; Mott et al. 2009; Collins et al. 2012; Nunes et al. 2010; Santerre et al. 2012; Randall et al. 2012; Pardo et al. 2020), and MSX-3 and preladenant reverse the effects of TBZ (Nunes et al. 2013; Randall et al. 2014; Yohn et al. 2015a; Salamone et al. 2018). [...] Furthermore, A2A receptor knockout mice are resistant to the effort-related effects of haloperidol (Pardo et al. 2012). [...] Along with adenosine A2A antagonists such as istradefylline and preladenant (Nunes et al. 2013; Randall et al. 2014; Yohn et al. 2015a; Salamone et al. 2018), and D1 agonists (Yohn et al. 2015b), atypical DAT inhibitors offer promise as potential treatments for effort-related motivational symptoms.

[TurnerHusain2022-6] Turner V, Husain M (2022). "Anhedonia in Neurodegenerative Diseases". Curr Top Behav Neurosci. 58: 255–277. doi:10.1007/7854_2022_352. PMID 35435648. Recently, PD patients have been treated with istradefylline, an adenosine A2A receptor antagonist used for treatment of motor symptoms. The drug was given to 14 PD patients for 12 weeks, measuring anhedonia, apathy and depression using the SHAPS, Apathy Scale and BDI. On istradefylline, SHAPS, Apathy Scale and BDI scores significantly reduced from baseline scores at 4-, 8- and 12-weeks, with mean SHAPS scores at week 12 about 50% reduced from baseline scores, indicating that istradefylline reduces anhedonia (Nagayama et al. 2019). As apathy and depression rates dropped as well as anhedonia, this trial also provided evidence for the overlapping relationship between the three symptoms. [...] Taken together, there is some evidence that dopamine agonists such as pramipexole and piribedil, or the adenosine A2A receptor antagonist istradefylline can improve anhedonia and apathy in PD.

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