Prediction of Young's modulus of trabeculae in microscale using macro-scale's relationships between bone density and mechanical properties

According to the literature, there are many mathematical relationships between density of the trabecular bone and mechanical properties obtained in macro-scale testing. In micro-scale, the measurements provide only the ranges of Young's modulus of trabeculae, but there are no experimentally tested relationships allowing the calculation of the distribution of Young's modulus of trabeculae within these experimental ranges. This study examined the applicability of relationships between bone density and mechanical properties obtained in macro-scale testing for the calculation of Young's modulus distribution in micro-scale. Twelve cubic specimens from eleven femoral heads were cut out and micro-computed tomography (micro-CT) scanned. A mechanical compression test and Digital Image Correlation (DIC) measurements were performed to obtain the experimental displacement and strain full-field evaluation for each specimen. Five relationships between bone density and Young's modulus were selected for the test; those were given by Carter and Hayes (1977), Ciarelli et al. (2000), Kaneko et al. (2004), Keller (1994) for the human femur, and Li and Aspden, 1997. Using these relationships, five separate finite element (FE) models were prepared, with different distribution of Young's modulus of trabeculae for each specimen. In total, 60 FE analyses were carried out. The obtained displacement and strain full-field measurements from numerical calculations and experiment were compared. The results indicate that the highest accuracy of the numerical calculation was obtained for the Ciarelli et al. (2000) relationship, where the relative error was 17.87% for displacements and 50.94 % for strains. Therefore, the application of the Ciarelli et al. (2000) relationship in the microscale linear FE analysis is possible, but mainly to determine bone displacement

A dual-acting 5-HT 6 receptor inverse agonist/MAO-B inhibitor displays glioprotective and pro-cognitive properties

International audienceThe complex etiology of Alzheimer's disease has initiated a quest for multi-target ligands to address the multifactorial causes of this neurodegenerative disorder. In this context, we designed dual-acting 5-HT6 receptor (5-HT6R) antagonists/MAO-B inhibitors using pharmacophore hybridization strategy. Our approach involved linking 5-HT6R scaffolds with aryloxy fragments derived from reversible and irreversible MAO-B inhibitors. The study identified compound 48 that acts as an inverse agonist of 5-HT6R at Gs signaling and an irreversible MAO-B inhibitor. Compound 48 showed moderate metabolic stability in rat microsomal assay and artificial membrane permeability, and it was well distributed to the brain. Additionally, 48 showed glioprotective properties in a model of cultured astrocytes using 6-OHDA as the cytotoxic agent. Finally, compound 48 (MED = 1 mg/kg, p.o.) fully reversed memory deficits in the NOR task induced by scopolamine in rats. A better understanding of effects exerted by dual-acting 5-HT6R/MAO-B modulators may impact the future development of neurodegenerative-directed treatment strategies

Dual 5−HT65-HT_6 and D3D_3 receptor antagonists in a group of 1H-pyrrolo[3,2-c]quinolines with neuroprotective and procognitive activity

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A PDE10A inhibitor CPL500036 is a novel agent modulating striatal function devoid of most neuroleptic side-effects

Background: Phosphodiesterase 10A (PDE10A) is expressed almost exclusively in the striatum and its inhibition is suggested to offer potential treatment in disorders associated with basal ganglia. We evaluated the selectivity, cytotoxicity, genotoxicity, pharmacokinetics and potential adverse effects of a novel PDE10A inhibitor, CPL500036, in vivo. Methods: The potency of CPL500036 was demonstrated by microfluidic technology, and selectivity was investigated in a radioligand binding assay against 44 targets. Cardiotoxicity in vitro was evaluated in human ether-a-go-go related gene (hERG)-potassium channel-overexpressing cells by the patch-clamp method and by assessing key parameters in 3D cardiac spheroids. Cytotoxicity was determined in H1299, HepG2 and SH-SY5Y cell lines. The Ames test was used for genotoxicity analyses. During in vivo studies, CPL500036 was administered by oral gavage. CPL500036 exposure were determined by liquid chromatography–tandem mass spectrometry and plasma protein binding was assessed. The bar test was employed to assess catalepsy. Prolactin and glucose levels in rat blood were measured by ELISAs and glucometers, respectively. Cardiovascular safety in vivo was investigated in dogs using a telemetry method. Results: CPL500036 inhibited PDE10A at an IC(50) of 1 nM, and interacted only with the muscarinic M2 receptor as a negative allosteric modulator with an IC(50) of 9.2 µM. Despite inhibiting hERG tail current at an IC(25) of 3.2 μM, cardiovascular adverse effects were not observed in human cardiac 3D spheroids or in vivo. Cytotoxicity in vitro was observed only at > 60 μM and genotoxicity was not recorded during the Ames test. CPL500036 presented good bioavailability and penetration into the brain. CPL500036 elicited catalepsy at 0.6 mg/kg, but hyperprolactinemia or hyperglycemic effects were not observed in doses up to 3 mg/kg. Conclusion: CPL500036 is a potent, selective and orally bioavailable PDE10A inhibitor with a good safety profile distinct from marketed antipsychotics. CPL500036 may be a compelling drug candidate

2-Phenyl-1 H -pyrrole-3-carboxamide as a New Scaffold for Developing 5-HT 6 Receptor Inverse Agonists with Cognition-Enhancing Activity

International audienceSerotonin type 6 receptor (5-HT6R) has gained particular interest as a promising target for treating cognitive deficits, given the positive effects of its antagonists in a wide range of memory impairment paradigms. Herein, we report on degradation of the 1H-pyrrolo[3,2-c]quinoline scaffold to provide the 2-phenyl-1H-pyrrole-3-carboxamide, which is devoid of canonical indole-like skeleton and retains recognition of 5-HT6R. This modification has changed the compound's activity at 5-HT6R-operated signaling pathways from neutral antagonism to inverse agonism. The study identified compound 27 that behaves as an inverse agonist of the 5-HT6R at the Gs and Cdk5 signaling pathways. Compound 27 showed high selectivity and metabolic stability and was brain penetrant. Finally, 27 reversed scopolamine-induced memory decline in the novel object recognition test and exhibited procognitive properties in the attentional set-shifting task in rats. In light of these findings, 27 might be considered for further evaluation as a new cognition-enhancing agent, while 2-phenyl-1H-pyrrole-3-carboxamide might be used as a template for designing 5-HT6R inverse agonists

Overcoming undesirable hERG affinity by incorporating fluorine atoms: A case of MAO-B inhibitors derived from 1 H-pyrrolo-[3,2-c]quinolines

International audienceThe incorporation of the fluorine motif is a strategy widely applied in drug design for modulating the activity, physicochemical parameters, and metabolic stability of chemical compounds. In this study, we attempted to reduce the affinity for ether-à-go-go-related gene (hERG) channel by introducing fluorine atoms in a group of 1H-pyrrolo[3,2-c]quinolines that are capable of inhibiting monoamine oxidase type B (MAO-B). A series of structural modifications guided by in vitro evaluation of MAO-B inhibition and antitargeting for hERG channels were performed, which led to the identification of 1-(3-chlorobenzyl)-4-(4,4-difluoropiperidin-1-yl)-1H-pyrrolo[3,2-c]quinoline (26). Compound 26 acted as a reversible MAO-B inhibitor exhibiting selectivity over 45 targets, enzymes, transporters, and ion channels, and showed potent glioprotective properties in cultured astrocytes. In addition, the compound demonstrated good metabolic stability in rat liver microsomes assay, a favorable safety profile, and brain permeability. It also displayed procognitive effects in the novel object recognition test in rats and antidepressant-like activity in forced swim test in mice. The findings of the study suggest that reversible MAO-B inhibitors can have potential therapeutic applications in Alzheimer's disease