Adenosine receptor affinity of methoxy-substituted 2-benzylidene-1-indanone derivatives for the potential treatment of depression

Abstract

Depression is a debilitating mental illness associated with feelings of despair. It can cause structural and chemical changes in the brain and significantly impact the quality of life of many people worldwide. Often, depression and anxiety can develop co-morbidly in patients and are said to affect as much as one-quarter of all patients in general healthcare. Not only can untreated depression lead to suicide, but it is also associated with a much-increased risk of developing other severe medical conditions like type 2 diabetes or breast cancer. The range of treatment options for depression has grown throughout the years. Still, current treatment is said to reach desired outcomes in only about 50% of patients, with primary concerns including delayed onset of action and possible side effects. This leaves room for the development of new drugs that focus on different depression-causing mechanisms in the brain and even possible dual drug targets. The involvement of complex and intertwined neurotransmitter signalling pathways and the hypothalamic-pituitary-adrenal (HPA) axis in depression permits ongoing research. This study mainly focuses on the neuromodulators, adenosine and serotonin (5-HT), which play a role in the regulation of mood and can be associated with depression and anxiety, as well as the enzyme glycogen synthase kinase-3 beta (GSK-3β) associated with inflammation which can influence serotonin and dopamine levels. Research shows that nonselective antagonism of the adenosine A1 and A2A receptors can alleviate depressive symptoms. Furthermore, the serotonin transporter (SERT) regulates serotonin reuptake in the synaptic cleft. Current antidepressants inhibit the SERT, which leads to increased extracellular serotonin levels. Interconnected pathways may regulate both adenosine and serotonin levels concurrently in the brain; thus, SERT inhibitors and adenose A1 and A2A receptor antagonists can be explored as dual drug targets for the treatment of depression and anxiety. The GSK-3β enzyme also plays a role in a variety of signalling pathways, mainly interlinked to serotonin and ultimately present in higher levels in patients with depression, making GSK-3β inhibition another possibility for the treatment of this condition. This study aimed to synthesise eight novel C4-methoxy substituted 2-benzylidene-1-indanone derivates 2i-p to complete a series of previously synthesised compounds with promising adenosine A1 and A2A receptor binding activity. Nuclear magnetic resonance (NMR) spectroscopy, mass spectrometry (MS), high-performance liquid chromatography (HPLC) and melting points were used to characterise and determine the purity of these compounds. Radioligand binding assays determined that the novel compounds 2i-p lacked affinity towards the adenosine A1 and A2A receptors, which may be caused by the addition of halogens (Br, Cl, F), CF3 or CN groups on positions C3' and/or C4' of the benzylidene ring. Previously synthesised compounds 2c and 2e, containing a C4-methoxy group on ring A and hydroxy substitution(s) on the benzylidene ring, have the overall best dual adenosine A1/A2A activity within the series. The series comprising 2-benzylidene-1-indanone derivatives 1a-p and 2a-p were tested for SERT affinity and GSK-3β inhibition potential. No compounds showed likely binding to the SERT, but various compounds showed promising potential GSK-3β inhibition. The C4-methoxy substituted 2n containing a fluorine atom at the C4' or para position on ring B was the top performer in the GSK-3β inhibition assay, exhibiting the highest inhibition, making it the strongest candidate for further investigation. Interestingly, other research studies also found that a fluorine or methoxy-substituted hydrophobic moiety, especially bulky aryl halide substituents, leads to potent GSK-3β inhibitors. The current study was limited by using a single concentration to determine GSK-3β inhibition, and further testing across multiple concentrations is necessary to determine IC50 values and more accurately assess structure-activity relationships. This leaves room for further investigation of the 2-benzylide-1-indanone scaffold with the possibility of structural improvement to yield more potent GSK-3β inhibitors and the possibility of developing a novel treatment option for depression.