Exploring the 2- and 5-positions of the pyrazolo[4,3-d]pyrimidin-7-amino scaffold to target human A1 and A2A adenosine receptors

Methoxy substituted 2-benzylidene-1-indanone derivatives as A1 and/or A2A AR antagonists for the potential treatment of neurological conditions

“…The affinities of the 2-benzylidene-1-indanone analogues (2a-m) at rat A 1 and A 2A AR subtypes were determined with radioligand competition experiments as described previously. 22,23 The competition experiments were carried out in the presence of the radioligands for the A 1 and A 2A AR radioligand binding assays, respectively. 22,24 In addition, the A 2A AR binding studies were determined in the presence of N 6 -cyclopentyladenosine (CPA) to minimize the binding of [ 3 H]NECA to A 1 AR's.…”

“…The GTP shift assay was performed as described previously with rat whole brain membranes and [ 3 H]DPCPX (0.1 nM; K d = 0.36 nM) in the absence and presence of a final concentration of 100 μM GTP (see Table 2). 22,23 Non-specific binding was defined by the addition of 10 μM DPCPX (unlabelled). If a calculated GTP shift of approximately 1 is obtained, that compound is considered to function as an antagonist.…”

“…18 The investigation of dual A 1 /A 2A AR antagonists for the potential treatment of PD has been investigated in the past. [19][20][21][22][23] For example, 5-[5-amino-3-(4-fluorophenyl)pyrazin-2-yl]-1isopropylpyridine-2IJ1H)-one (ASP5854) (see Fig. 1) showed promise in animal models of PD as well as cognition and has K i values of 9.03 nM at the human A 1 AR and 1.76 at the human A 2A AR.…”

“…22 The 7-aminopyrazoloij4,3-d]pyrimidine derivatives were also explored as dual A 1 /A 2A AR antagonists with several of these compounds possessing nanomolar affinity for the human A 2A AR and slightly lower human A 1 AR. 23 Therefore, dual A 1 and A 2A AR antagonists may be nondopaminergic drugs for the symptomatic treatment of both PD motor symptoms (for example bradykinesia, rigidity, resting tremor and postural instability) and PD non-motor symptoms (for example cognitive deficits such as cognitive dysfunction and depression) as well as exhibit neuroprotective properties. 4 Benzopyrones are a class of compounds with significantly diverse biological activities 24 (including antiparkinsonian and neuroprotective properties) [25][26][27][28][29][30] and are, thus, considered a privileged scaffold in medicinal chemistry.…”

Design and Synthesis of Novel Thiazolo[5,4-d]pyrimidine Derivatives with High Affinity for Both the Adenosine A1 and A2A Receptors, and Efficacy in Animal Models of Depression

“…Our efforts in the pursuit of novel AR antagonists have centered on mono- or bicyclic heteroaromatic systems. [ 26 , 27 , 28 , 29 , 30 ]. Within this research, an interesting class of antagonists/inverse agonists (i.e., the thiazolo[5,4-d]pyrimidine series) was identified [ 31 , 32 , 33 , 34 , 35 ].…”