br Conflict of interest br Acknowledgement This study was su

Conflict of interest
Acknowledgement This study was supported by a grant from University Grants Commission - Basic Scientific Research (UGC-BSR), New Delhi, India (UGC-BSR No:F-7-115/2007).
Introduction The G protein-coupled receptors activated by extracellular adenosine (Ado), called Adenosine receptors (ARs), are widely expressed in the organism as four subtypes, namely A1, A2A, A2B, and A3 ARs [1,2]. Due to the involvement of these membrane proteins at different levels in a number of physiological functions and pathological conditions, the development of selective ligands (agonists, antagonists, inverse agonists, and allosteric modulators) for AR subtypes represents a hot topic in medicinal chemistry. In particular, while A1AR agonists are of interest for their cardioprotective, cerebroprotective, and antinociceptive properties or for the treatment of diabetes (partial agonists) [[3], [4], [5]], antagonists of this AR subtype are evaluated for a possible therapeutic application as diuretics and antihypertensives, or for their beneficial role in heart failure, allergy, and find more info modulation [[6], [7], [8], [9], [10], [11], [12], [13], [14], [15], [16], [17]]. It has been widely reported that A1ARs are involved in the modulation of the intestinal motility. In particular, the activation of this receptor leads to an inhibition of the propulsive motor activity of ileus. Conversely, blocking of the same receptor by antagonists restores the normal motility function without any induction of diarrhea. These data suggest the administration of A1AR antagonists as a potential therapeutic strategy for various functional motility syndromes in the colon, including constipation and postoperative ileus [[18], [19], [20], [21], [22]]. A prototypical scaffold used to obtain A1AR antagonists is the xanthine moiety, with the introduction of two alkyl chains to the N1 and N3 nitrogen atoms and a bulky and generally hydrophobic group in 8-position [23]. This plot led to the development of A1AR antagonists like DPCPX, BG 9719, BG 9928, and KW 3902 (1-1c, respectively, Chart 1) that represent reference molecules for pharmacological studies at the A1AR and/or have been evaluated in various clinical trials [24]. Among them, BG 9719 (1a, also named naxifylline or CVT 124) was developed by Biogen Inc. for the treatment of congestive heart failure with concomitant renal impairment, where it protected against decline in renal function. The molecule is endowed with an affinity at the human (h) A1AR of 10.3 nM and selectivity versus the other AR subtypes [25]. Unfortunately, it was withdrawn after phase 2 clinical trials because it lowered seizure threshold [8,26]. The same company similarly evaluated the oral drug BG 9928 [27] (1b, also named tonapofylline) in two large pivotal Phase 2 trials (POSEIDON and TRIDENT-1) aiming at improving natriuresis and volume loss in high-risk patients with acute decompensated heart failure. Results from these studies showed lack of statistical difference between treated and controlled groups in regards to body weight change, improved dyspnea, worsened renal function, and length of hospital stay, alongside inducing a 1% risk of seizure [16,28]. This outcome, in conjunction with the clinical failure of another A1AR antagonist KW 3902 [29] (1c, also named rolofylline and MK7418) in a Phase 3 trial by NovoCardia Inc. and Merck & Co. Inc., aroused concerns about the clinical safety and efficacy of A1 antagonists in the treatment of a broad range of patients with heart failure [30]. On the other hand, A1AR antagonists were developed also based on various non-xanthine scaffolds [31] such as purines [32], imidazopurinones [33], pyrazolopyrimidines [34], pyrazolopyridines [35], naphthyridines [36], pyrimidoindoles [37], thiazoles [38], pyrimidines [39], pyrazoles [40], benzimidazolquinolines [41], and pyrazolopyrimidopyridazones [42] as examples. Even in these cases, the compounds present one or more bulky and hydrophobic groups that (like for the above cited xanthine derivatives) appear to generally provide affinity for the A1AR and selectivity versus the other AR subtypes.