Anxiolytic properties of A1 adenosine receptor PAMs

Anxiety and anxiety disorders are among the most prevalent mental health conditions worldwide. Despite the high prevalence rates, anxiety is often an underestimated and undertreated clinical problem. Current treatment strategy for the management of anxiety mainly involves the use of selective serotonin reuptake inhibitors and benzodiazepines. Although widely prescribed and effective in reducing acute anxiety, benzodiazepines are associated with different adverse effects such as impaired cognition and coordination, physiological and psychological dependence, sedation, and memory loss [1]. Furthermore, they have a potential risk of overdose/intoxication when mixed with other central nervous system (CNS) depressant such as alcohol or opioids. For these reasons, safer and fast-acting therapeutic alternatives are highly desirable. Various studies suggested the involvement of adenosine in the regulation of anxious states. Adenosine is a ubiquitous nucleoside that acts as a neuromodulator in the CNS, controlling neuronal excitability and modulating neurotransmitter release [2]. The action of adenosine is mediated by four G-protein coupled receptors named as A 1 , A 2 A, A 2 B and A 3 subtypes. Several works have identified A 1 adenosine receptors (ARs) as potential target for the development of novel strategies in the management of anxiety. In particular, enhanced anxiety has been observed in A 1 ARs knockout mice. Interestingly, electrophysiological recordings from hippocampal slices revealed that adenosine-mediated inhibition of excitatory glutamatergic neurotransmission were abolished in A 1 ARs knockout mice [3]. Previous work have demonstrated the anxiolytic-like effect of A 1 AR activation by means of the well-known agonist CCPA [4]. Despite their promising therapeutic potential, the use of A 1 AR agonists has been hampered by numerous side effects, poor receptor subtype selectivity and receptor desensitization. To overcome the problems associated with the utilization of A 1 AR agonists, we have developed a series of positive allosteric modulators (PAMs) as a potential alternative for A 1 ARs-targeted therapies [5]. Allosteric receptor modulation represents an attractive concept in drug targeting offering remarkable potential advantages over conventional agonists. In particular, since PAMs enhance the effect of endogenous agonists, they are expected to have a much lower side effect potential than orthosteric agonists, a low propensity for receptor desensitization and a high selectivity for a given receptor subtype. TRR469 is one of the most potent PAMs for A 1 ARs so far synthetized. In a previous work, we have demonstrated the anti-nociceptive effects of TRR469 in two models of acute pain such as writhing …