1H-Pyrazolo[3,4-g]hexahydro-isoquinolines as potent GR antagonists with reduced hERG inhibition and an improved pharmacokinetic profile

Glucocorticoid receptors signaling impairment potentiates amyloid‐β oligomers‐induced pathology in an acute model of Alzheimer’s disease

“…3,4 The HPA axis, highly involved in the stress response, triggers the adrenal cortex to release GC. 11 In an acute pathomimetic model of AD obtained after a single intracerebroventricular (icv) injection of an oligomeric solution of Aβ (oAβ [25][26][27][28][29][30][31][32][33][34][35], [12][13][14] we demonstrated a strong, long-lasting activation of the HPA axis, associated with a modification of GR and MR expression in brain regions involved in the control of GC secretion (hippocampus, amygdala, and hypothalamus), 15 supporting its involvement in the etiology of AD. 5 GC are necessary for normal cellular activity and fundamental for many CNS functions, including learning and memory.…”

“…These steroid hormones readily cross the BBB and bind to low-affinity glucocorticoid receptors (GR) and high-affinity mineralocorticoid receptors (MR). 9,[16][17][18][19] We also observed that an antagonist and selective modulators of the GR could potently counteract the effects of oAβ [25][26][27][28][29][30][31][32][33][34][35] injection in the hippocampus, arguing strongly for a therapeutic potential of modulating GR activity. 6 While MR are localized mainly in the hippocampus, GR are more ubiquitous and are particularly found in several structures of the limbic system (prefrontal cortex [PFC], hippocampus, and amygdala), which are strongly involved in cognitive and psychological functions but also are important components of the neural circuitry modulating HPA axis activity.…”

“…Behavioral deficits, observed 2 weeks after oAβ [25][26][27][28][29][30][31][32][33][34][35] , were associated with pre-(SYN) and post-synaptic (PSD95) deficits, increased apoptotic marker expression (Figure 2A-D) and a marked neuroinflammation characterized by the activation of astrocytes (GFAP) (Figure 2A,E) and microglial cells (Iba1) (Figure 2A,F). 30 To determine in the PFC the effects of oAβ [25][26][27][28][29][30][31][32][33][34][35] (and of CORT113176) on glucocorticoid receptor signaling, as part of a potential feed-forward or feedback process, animals were treated as previously detailed ( Figure 1A). 30 To determine in the PFC the effects of oAβ [25][26][27][28][29][30][31][32][33][34][35] (and of CORT113176) on glucocorticoid receptor signaling, as part of a potential feed-forward or feedback process, animals were treated as previously detailed ( Figure 1A).…”

“…CORT113176 (10 mg/kg b.w. One group has not undergone surgery (control rats, white column), a second group received an icv injection of scrambled Aβ 25-35 peptide (negative control-10 µg/rat-orange column) and a third group received an icv injection of oAβ [25][26][27][28][29][30][31][32][33][34][35] peptide (Aβ-0 µg/rat-red column). The short-term memory or anxiety state of different groups of rats were tested (day 14) in a T-maze or in an elevated plus maze test (EPM), respectively.…”

“…36 Interest in this undecapeptide, which itself shows a β-sheet structure, 12,36 has grown over the last decade, mainly because it induces neurite atrophy, neuronal cell death, synaptic loss, as well as synaptic plasticity and memory deficits in a similar way to Aβ 1-40 and Aβ 1-42 , 37 but with better solubility and efficiency. Since soluble Aβ oligomers correlate better with the progression of the disease, 40 Aβ 25-35 and scrambled peptides were aggregated by in vitro incubation at 37°C (4 days) to obtain a solution mainly composed (more than 95%) of a mixture of soluble oligomer species (oAβ [25][26][27][28][29][30][31][32][33][34][35], as previously characterized. Since soluble Aβ oligomers correlate better with the progression of the disease, 40 Aβ 25-35 and scrambled peptides were aggregated by in vitro incubation at 37°C (4 days) to obtain a solution mainly composed (more than 95%) of a mixture of soluble oligomer species (oAβ [25][26][27][28][29][30][31][32][33][34][35], as previously characterized.…”