Adenosine receptors as drug targets — what are the challenges?

Abstract

Adenosine signalling has long been a target for drug development, with adenosine itself or its derivatives being used clinically since the 1940s. In addition, methylxanthines such as caffeine have profound biological effects as antagonists at adenosine receptors. Moreover, drugs such as dipyridamole and methotrexate act by enhancing the activation of adenosine receptors. There is strong evidence that adenosine has a functional role in many diseases, and several pharmacological compounds specifically targeting individual adenosine receptors — either directly or indirectly — have now entered the clinic. However, only one adenosine receptor-specific agent — the adenosine A2A receptor agonist regadenoson (Lexiscan; Astellas Pharma) — has so far gained approval from the US Food and Drug Administration (FDA). Here, we focus on the biology of adenosine signalling to identify hurdles in the development of additional pharmacological compounds targeting adenosine receptors and discuss strategies to overcome these challenges.

Expression of mediators of purinergic signaling in human liver cell lines

“…For instance, purinergic signals regulate proliferation [12][13][14] and glucose release [15] in hepatocytes; secretion [16,17], proliferation [18], and mechanosensation [19] in cholangiocytes; and fibrogenic activity [20,21] and properties in HSC [22,23]. Of note, the purinergic signaling system is quite diverse, including multiple subtypes of G proteincoupled receptors for adenosine P1 receptors [24] and nucleotide P2Y receptors [25], nucleotide P2X ligand-gated ion channels [26], and a variety of plasma membrane-bound ecto-enzymes that regulate extracellular nucleotide/ nucleoside levels, namely ecto-nucleoside triphosphate diphosphohydrolases (ENTPDases) [27,28], CD73/ecto-5′-nucleotidase [29,30], and tissue-non-specific alkaline phosphatase (TNAP) [31]. Thus, there is tremendous, almost overwhelming, complexity both in the relevant cell types and purinergic signaling systems relevant to liver physiology and disease [32].…”

PQ-69, a novel and selective adenosine A1 receptor antagonist with inverse agonist activity

“…Adenosine is an important endogenous modulator with a large variety of physiological functions acting on four different adenosine receptor (AR) subtypes, named A 1 , A 2A , A 2B and A 3 . Upon activation, A 1 and A 3 AR may inhibit adenylyl cyclase, which results in a decrease in cyclic AMP level and stimulates phospholipase C and phospholipase D via G i/o protein, whereas the A 2A and A 2B ARs are stimulatory to adenylyl cyclase via G s protein.…”

“…A 1 ARs are expressed in large numbers in the brain, as well as in peripheral tissues including kidney, heart and liver [2]. Because of adenosine exerting different physiological effects, a large number of A 1 AR antagonists exhibit a plethora of actions including anti-hypertensive, anti-depressive, anti-diabetic, anti-Parkinson and anti-hyperanalgesic effects [3]. In the kidney, the importance of A 1 ARs has been confirmed in regulation of fluid balance [4].…”

Pharmacological targeting of adenosine receptor signaling

“…This means that a given type of adenosine receptor is going to be present not only on the target cell(s) involved in a disease process, but also on cells that are involved in very diverse physiological processes. This problem is accentuated with promiscuous agonists, which activate all receptors, than with antagonists selective to cells with substantial ongoing activation (Chen et al, 2013).…”

“…Since adenosine receptor-mediated signaling plays a role in modulating the progression of various pathological disorders, the creation of efficient and safe pharmacological ligands has considerable therapeutic potential, but is fraught with difficulty (Chen et al 2013). Efforts in medicinal and organic chemistry have been fruitful and numerous adenosine analogues with high affinity and selectivity have been generated (Fredholm et al, 2001;Fredholm et al, 2011).…”