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| Other names | SCH-420814 |
| Routes of administration | By mouth |
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| ECHA InfoCard | 100.210.813 |
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| Formula | C25H29N9O3 |
| Molar mass | 503.567 g·mol−1 |
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Preladenant (developmental code nameSCH-420814) is a drug that was developed bySchering-Plough which acts as apotent andselectiveantagonist of theadenosineA2A receptor.[1] It was being researched as a potential treatment forParkinson's disease.[2] Positive results were reported in Phase IIclinical 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 highaffinity for the A2A receptor (<1 nM) and shows more than 1,000-foldselectivity for the A2A receptor over the otheradenosine receptors.[1][5]
Preladenant showspro-motivational effects in animals and reversestetrabenazine-inducedmotivational deficits.[1][6] Other A2A receptor antagonists, includingistradefylline,Lu AA47070,MSX-3, andMSX-4, have also shown such effects.[1][6] These agents may be useful in the treatment ofmotivational disorders in humans.[1][6] Accordingly, istradefylline has been reported to reduceapathy,anhedonia,fatigue, anddepression in people withParkinson's disease.[7][1]
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.
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.