Development of Polar Adenosine A_2A Receptor Agonists for Inflammatory Bowel Disease: Synergism with A_2B Antagonists

Abstract

Adenosine A 2A receptor agonists for the local treatment of inflammatory bowel disease (IBS) were designed and synthesized. Polar groups were introduced to prevent peroral absorption and subsequent systemic, e.g., hypotensive, side effects. 4-(2-{6-Amino-9-[(2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl]-9H-purin-2-ylthio}ethyl)-benzenesulfonic acid (7, PSB-0777) was selected for further evaluation in rat ileum/jejunum preparations in ex vivo experiments. Compound 7 significantly improved impaired acetylcholine-induced contractions induced by 2,4,6-trinitrobenzenesulfonic acid and showed synergism with an A 2B -selective antagonist. Thus, nonabsorbable, locally active A 2A agonists, as a monotherapy or in combination with an A 2B antagonist, may be an efficient novel treatment for IBS, preventing the severe systemic side effects of known A 2A agonists. Activation of the A 2A AR on a variety of inflammatory cell types leads to anti-inflammatory effects that can attenuate injury as a result of mucosal inflammation, ischemia, or sepsis. Adenosine, being part of the innate immune system, is one of the strongest endogenous immunosuppressive agents. Therefore, A 2A AR agonists have been suggested as novel antiinflammatory drugs. 2,6,7 Inflammatory bowel disease (IBD) is an inflammatory condition in the gastrointestinal tract. A 2A AR agonists have had beneficial effects on the development of intestinal inflammation in a variety of animal models of IBD, including Crohn's disease, colitis, and irritable bowel disease, as well as other inflammatory conditions. 8−11 However, the systemic use of A 2A adenosine receptor agonists as anti-inflammatory drugs is limited by their potent hypotensive activity caused by the activation of A 2A AR expressed in heart and blood vessels. 1,7 Received: August 8, 2011 Accepted: October 10, 2011 Published: October 10, 2011

Anti-inflammatory effect of a novel locally acting A2A receptor agonist in a rat model of oxazolone-induced colitis

“…In parallel, experiments performed on CaCo-2 cell monolayers, aimed at investigating the level of PSB-0777 penetration, displayed a lack of absorption of this A 2A agonist. This evidence is consistent with the chemical properties of PSB-0777 [16]. Indeed, as reported by ElTayeb et al [16], this compound, besides being endowed with high affinity for A 2A receptors and high selectivity (> 225-fold) over the other adenosine receptors, is endowed with a high polar structure, which confers to the compound high solubility in water and a lack of permeability across cell membranes.…”

“…This evidence is consistent with the chemical properties of PSB-0777 [16]. Indeed, as reported by ElTayeb et al [16], this compound, besides being endowed with high affinity for A 2A receptors and high selectivity (> 225-fold) over the other adenosine receptors, is endowed with a high polar structure, which confers to the compound high solubility in water and a lack of permeability across cell membranes. These physico-chemical features of PSB-0777 account for its scarce systemic bioavailability upon oral administration, as documented by our in vivo experiments.…”

“…The synthesis of PSB-0777 was performed as previously reported by El Tayeb et al [16]. For oral gavage administration, PSB-0777 and dexamethasone were suspended in 1% methocel (Sigma Chemicals, Saint Louis, MO, USA) and administered in a volume of 0.5 ml per rat.…”

“…For these reasons, intensive efforts are being focused on the design of novel agonists aimed at channeling the A 2A -mediated anti-inflammatory/immunomodulatory effects specifically towards the inflammatory environment. Along this line, interesting results have been recently pursued by Müller and coworkers [16] through the development of PSB-0777, a novel highly polar A 2A -selective agonist, which cannot be absorbed systemically by the digestive mucosa once administered by the oral route.…”

BAY60-6583 Acts as a Partial Agonist at Adenosine A2B Receptors

“…On the other hand, the blockade of A 2B ARs was also shown to lead to anti-inflammatory effects. Therefore, A 2B -selective antagonists were proposed as a novel approach for the management and treatment of asthma and chronic obstructive pulmonary disease (Kalla et al, 2006Elzein et al, 2008), intestinal inflammation (Kolachala et al, 2008;El-Tayeb et al, 2011), and inflammatory pain (Bilkei-Gorzo et al, 2008).…”