Novel dual D3R/GSK-3β modulators: an innovative multitarget strategy for bipolar disorder

Among the psychiatric diseases, bipolar disorder (BD) is the sixth leading cause of disability with a prevalence up to 4 % worldwide. BD is a complex neuropsychiatric condition which alternates episodes of mania with symptoms of depression. Although the neurobiological pathways are not completely clarified, the dopamine (DA) hypothesis, recognized as the leading theory explaining the pathophysiology of the malady, states that the dramatically compromised homeostatic regulation of dopaminergic circuits leads to alternated changes in DA neurotransmission. Modulation of D2 and D3 receptors (D2/3R) through partial agonists represents the first-line therapeutic strategy for psychiatric diseases. Moreover, a deregulation of the enzyme glycogen synthase kinase-3β (GSK-3β) has been reported as peculiar feature of BD. In this scenario, the concomitant modulation of D3R and GSK-3β, by employing multitarget compounds, could offer promises to achieve an effective cure of this illness. In the light of these findings, we rationally envisaged the pharmacophoric model at the basis of the design of several D3R partial agonists, suitable to be exploited for the dual D3R/GSK-3β ligand design. Thus, synthetic efforts were addressed to develop a first set of hybrid molecules able to concurrently modulate the selected targets. For a chemical structure point of view, we employed different spacers to combine a substituted aryl-piperazine moiety, reported in previously discovered D3R modulators, with a pyrazole-based fragment, already identified in GSK-3β inhibitors. A fluorescent and a cellular functional assays were carried out to assess the activity of all synthetized compounds against GSK-3β and on D3R, respectively. Most of the derivatives proved to effectively modulate both GSK-3β and D3R with potencies in the low-µM and low-nM range, respectively. The consistent biological data allowed us to identify some lead candidates worth to be further modified with the aim to optimize their biological profile and to perform a structure-activity relationship (SAR) study.

The mesophotic zone of the Mediterranean Sea: spatial definition, biodiversity, and predictive models

The mesophotic zone is frequently defined as ranging between 30-40 and 150 m depth. However, these borders are necessarily imprecise due to variations in the penetration of light along the water column related to local factors. Moreover, density of data on mesophotic ecosystems vary along geographical distance, with temperate latitudes largely less explored than tropical situations. This is the case of the Mediterranean Sea, where information on mesophotic ecosystems is largely lower with respect to tropical situations. The lack of a clear definition of the borders of the mesophotic zone may represent a problem when information must be transferred to the policy that requires a coherent spatial definition to plan proper management and conservation measures. The present thesis aims at providing information on the spatial definition of the mesophotic zone in the Mediterranean Sea, its biodiversity and distribution of its ecosystems. The first chapter analyzes information on mesophotic ecosystems in the Mediterranean Sea to identify gaps in the literature and map the mesophotic zone in the Mediterranean Sea using light penetration estimated from satellite data. In the second chapter, different visual techniques to study mesophotic ecosystems are compared to identify the best analytical method to estimate diversity and habitat extension. In the third chapter, a set of Remotely Operated vehicles (ROV) surveys performed on mesophotic assemblages in the Mediterranean Sea are analyzed to describe their taxonomic and functional diversity and environmental factors influencing their structure. A Habitat Suitability Model is run in the fourth chapter to map the distribution of areas suitable for the presence of deep-water oyster reefs in the Adriatic-Ionian area. The fifth chapter explores the mesophotic zone in the northern Gulf of Mexico providing its spatial and vertical extension of the mesophotic zone and information on the diversity associated with mesophotic ecosystems.