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Adrian Newmantancredi - One of the best experts on this subject based on the ideXlab platform.
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from Receptor selectivity to functional selectivity the rise of biased agonism in 5 ht1a Receptor drug discovery
Current Topics in Medicinal Chemistry, 2019Co-Authors: Joanna Sniecikowska, Adrian Newmantancredi, Marcin KolaczkowskiAbstract:Despite extensive efforts to design serotonin 5-HT1A Receptor compounds, there are currently no clinically available selective agonists to explore the therapeutic potential of activating this Receptor. Commonly used drugs targeting 5-HT1A Receptors, such as buspirone or other azapirone compounds, possess only limited selectivity over cross-reacting sites, act as partial agonists for 5-HT1A Receptor activation, and are metabolically labile, generating active metabolites. In addition, drug discovery has been hampered by the multiplicity of 5-HT1A Receptor subpopulations, expressed in different brain regions, that are coupled to distinct molecular signaling mechanisms and mediate a wide variety of physiological responses, both desired and undesired. In this context, advances in 5-HT1A Receptor drug discovery have attracted attention of novel 'biased agonists' that are selective, efficacious and preferentially target the brain regions that mediate therapeutic activity without triggering side effects. The prototypical first-in-class compound NLX-101 (a.k.a. F15599; 3-chloro-4-fluorophenyl-[4-fluoro-4-[[(5-methylpyrimidin-2-ylmethyl)amino]methyl]piperidin- 1-yl]methanone), preferentially activates 5-HT1A Receptors in cortical regions and exhibits potent, rapidacting and sustained antidepressant-like and procognitive properties in animal models. Here the background has been reviewed that led to the discovery of the class of 1-(1-benzoylpiperidin-4- yl)methanamine derivatives, including NLX-101, as well as recent advances in discovery of novel 5-HT1A Receptor biased agonists, notably aryloxyethyl derivatives of 1‑(1-benzoylpiperidin-4yl)methanamine which show promising pharmacological activity both in vitro and in vivo. Overall, the results suggest that opportunities exist for innovative drug discovery of selective 5-HT1A Receptor biased agonists that may open new avenues for the treatment of CNS disorders involving dysfunction of serotonergic neurotransmission.
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enhanced aggressive phenotype of tph2 knockout rats is associated with diminished 5 ht1a Receptor sensitivity
Neuropharmacology, 2019Co-Authors: Deborah G A Peeters, Adrian Newmantancredi, S.f. De ,boer, Anneke Terneusen, Mark A Varney, Robbertjan Verkes, Judith R HombergAbstract:Brain serotonin (5-HT) plays a key role in aggressive behaviours and related psychopathologies, but its precise mechanism of action remains elusive. Genetic animal models may provide a tool to elucidate the relationship between aggression and serotonin. The present study showed that tryptophan hydroxylase 2 (Tph2) knockout (KO) rats, which exhibit profoundly diminished extracellular serotonin levels, display increased aggressiveness compared to their Tph2 wildtype (WT) counterparts. However, the level of aggression in Tph2 KO rats did not equal that of feral wild type Groningen (WTG) rats. To investigate whether enhanced 5-HT1A Receptor functionality may be present in Tph2 KO rats, we tested the acute anti-aggressive potency of the highly selective 5-HT1A Receptor full agonist NLX-112 (a.k.a. befiradol or F13640). Data show that compared to Tph2 WT and WTG rats, the NLX-112 dose-effect curve was shifted to the right in Tph2 KO animals. These results suggest that, unlike previous reports in Tph2 KO mice, Tph2 KO rats have a decreased 5-HT1A Receptor sensitivity compared to both Tph2 WT and WTG animals.
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activity of serotonin 5 ht1a Receptor biased agonists in rat anxiolytic and antidepressant like properties
ACS Chemical Neuroscience, 2018Co-Authors: Magdalena Jastrzebskawiesek, Mark A Varney, Anna Partyka, Joanna Rychtyk, Marcin Kolaczkowski, Joanna śniecikowska, Anna Wesolowska, Adrian NewmantancrediAbstract:Although serotonin 5-HT1A Receptors constitute attractive therapeutic targets, there is a lack of potential clinical candidates that have a high degree of selectivity and full agonist efficacy. Recently, novel 5-HT1A Receptor "biased agonists" F15599 (also known as NLX-101) and F13714 have been reported that exhibit distinctive properties for in vitro signaling, neurochemical, electrophysiological effects, and in brain imaging. The present study characterized their effects in rat models of anxiety (elevated plus-maze, EPM, and Vogel tests), in depressive-like behavior (forced swim test), and on the induction of the three serotonergic behaviors (forepaw treading, flat body posture, and lower lip retraction). The prototypical 5-HT1A Receptor ligands (±)8-OH-DPAT and buspirone were tested as comparators. In the elevated plus-maze, F15599, F13714, and (±)8-OH-DPAT dose-dependently increased the amount and percentage of time spent in the open arms with minimal effective doses (MED) of 5 mg/kg p.o., 2.5 mg/kg p.o. and 1.25 mg/kg s.c., respectively. The effects of the three agonists were abolished by pretreatment with the selective 5-HT1A Receptor antagonist, WAY100635 (0.63 mg/kg s.c.). Buspirone did not show significant activity in the EPM. In contrast, in the Vogel test only buspirone was active, significantly increasing the number of licks and shocks accepted (active dose: 1.25 mg/kg s.c.). However, WAY100635 failed to reverse the effects of buspirone in this test, suggesting that they were not 5-HT1A Receptor-mediated. In the forced swim test, F15599, F13714, and (±)8-OH-DPAT were potently active, abolishing immobility (MED: 0.63 mg/kg p.o., 0.63 mg/kg p.o. and 0.16 mg/kg s.c., respectively). Buspirone was not active. In measures of serotonergic behavior, F13714 and (±)8-OH-DPAT robustly elicited all three signs of serotonergic behaviors, whereas F15599 and buspirone elicited only lower-lip retraction. Taken together, these observations highlight the distinct profiles of activity of 5-HT1A agonists and suggest that the novel biased agonist F15599 combines pronounced activity in a test of anxiety (elevated plus-maze) with potent antidepressant-like effects and low propensity to induce serotonergic behaviors. These data suggest that selective biased agonists could constitute promising pharmacotherapeutics for mood disorders.
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signal transduction and functional selectivity of f15599 a preferential post synaptic 5 ht1a Receptor agonist
British Journal of Pharmacology, 2009Co-Authors: Adrian Newmantancredi, Jeanclaude Martel, M B Assie, J Buritova, Emilie Lauressergues, Cristina Cosi, Peter Heusler, Bruins L Slot, Fc C Colpaert, Bernard VacherAbstract:Background and purpose: Activation of post-synaptic 5-HT1A Receptors may provide enhanced therapy against depression. We describe the signal transduction profile of F15599, a novel 5-HT1A Receptor agonist. Experimental approach: F15599 was compared with a chemical congener, F13714, and with (+)8-OH-DPAT in models of signal transduction in vitro and ex vivo. Key results: F15599 was highly selective for 5-HT1A Receptors in binding experiments and in [35S]-GTPγS autoradiography of rat brain, where F15599 increased labelling in regions expressing 5-HT1A Receptors. In cell lines expressing h5-HT1A Receptors, F15599 more potently stimulated extracellular signal-regulated kinase (ERK1/2) phosphorylation, compared with G-protein activation, internalization of h5-HT1A Receptors or inhibition of cAMP accumulation. F13714, (+)8-OH-DPAT and 5-HT displayed a different rank order of potency for these responses. F15599 stimulated [35S]-GTPγS binding more potently in frontal cortex than raphe. F15599, unlike 5-HT, more potently and efficaciously stimulated Gαi than Gαo activation. In rat prefrontal cortex (a region expressing post-synaptic 5-HT1A Receptors), F15599 potently activated ERK1/2 phosphorylation and strongly induced c-fos mRNA expression. In contrast, in raphe regions (expressing pre-synaptic 5-HT1A Receptors) F15599 only weakly or did not induce c-fos mRNA expression. Finally, despite its more modest affinity in vitro, F15599 bound to 5-HT1A Receptors in vivo almost as potently as F13714. Conclusions and implications: F15599 showed a distinctive activation profiles for 5-HT1A Receptor-mediated signalling pathways, unlike those of reference agonists and consistent with functional selectivity at 5-HT1A Receptors. In rat, F15599 potently activated signalling in prefrontal cortex, a feature likely to underlie its beneficial effects in models of depression and cognition.
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clozapine ziprasidone and aripiprazole but not haloperidol protect against kainic acid induced lesion of the striatum in mice in vivo role of 5 ht1a Receptor activation
Brain Research, 2005Co-Authors: Cristina Cosi, Aurelie Waget, Karin Rollet, Valentina Tesori, Adrian NewmantancrediAbstract:Excessive activation of non-NMDA Receptors, AMPA and kainate, contributes to neuronal degeneration in acute and progressive pathologies, possibly including schizophrenia. Because 5-HT1A Receptor agonists have neuroprotective properties (e.g., against NMDA-induced neurotoxicity), we compared the effects of the antipsychotics, clozapine, ziprasidone and aripiprazole, that are partial agonists at 5-HT1A Receptor, with those of haloperidol, which is devoid of 5-HT1A agonist properties, on kainic acid (KA)-induced striatal lesion volumes, in C57Bl/6N mice. The involvement of 5-HT1A Receptors was determined by antagonist studies with WAY100635, and data were compared with those obtained using the potent and high efficacy 5-HT1A Receptor agonist, F13714. Intra-striatal KA lesioning and measurement of lesion volumes using cresyl violet staining were carried out at 48 h after surgery. F13714, antipsychotics or vehicle were administered ip twice, 30 min before and 3 1/2 h after KA injection. WAY100635 (0.63 mg/kg) or vehicle were given sc 30 min before each drug injection. Clozapine (2 × 10 mg/kg), ziprasidone (2 × 20 mg/kg) and aripiprazole (2 × 10 mg/kg) decreased lesion volume by 61%, 59% and 73%, respectively. WAY100635 antagonized the effect of ziprasidone and of aripiprazole but only slightly attenuated that of clozapine. In contrast, haloperidol (2 × 0.16 mg/kg) did not affect KA-induced lesion volume. F13714 dose-dependently decreased lesion volume. The 61% decrease of lesion volume obtained with F13714 (2 × 0.63 mg/kg) was antagonized by WAY100635. WAY100635 alone did not affect lesion volume. These results show that 5-HT1A Receptor activation protects against KA-induced striatal lesions and indicate that some atypical antipsychotic agents with 5-HT1A agonist properties may protect against excitotoxic injury, in vivo.
Bryan D Bolinger - One of the best experts on this subject based on the ideXlab platform.
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the therapeutic efficacy conferred by the 5 ht1a Receptor agonist 8 hydroxy 2 di n propylamino tetralin 8 oh dpat after experimental traumatic brain injury is not mediated by concomitant hypothermia
Journal of Neurotrauma, 2004Co-Authors: Anthony E Kline, Jaime L Massucci, Edward C Dixon, Ross Zafonte, Bryan D BolingerAbstract:We recently reported that the 5-HT1A Receptor agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) attenuated traumatic brain injury (TBI)-induced cognitive deficits and histopathology. Howev...
Marcin Kolaczkowski - One of the best experts on this subject based on the ideXlab platform.
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from Receptor selectivity to functional selectivity the rise of biased agonism in 5 ht1a Receptor drug discovery
Current Topics in Medicinal Chemistry, 2019Co-Authors: Joanna Sniecikowska, Adrian Newmantancredi, Marcin KolaczkowskiAbstract:Despite extensive efforts to design serotonin 5-HT1A Receptor compounds, there are currently no clinically available selective agonists to explore the therapeutic potential of activating this Receptor. Commonly used drugs targeting 5-HT1A Receptors, such as buspirone or other azapirone compounds, possess only limited selectivity over cross-reacting sites, act as partial agonists for 5-HT1A Receptor activation, and are metabolically labile, generating active metabolites. In addition, drug discovery has been hampered by the multiplicity of 5-HT1A Receptor subpopulations, expressed in different brain regions, that are coupled to distinct molecular signaling mechanisms and mediate a wide variety of physiological responses, both desired and undesired. In this context, advances in 5-HT1A Receptor drug discovery have attracted attention of novel 'biased agonists' that are selective, efficacious and preferentially target the brain regions that mediate therapeutic activity without triggering side effects. The prototypical first-in-class compound NLX-101 (a.k.a. F15599; 3-chloro-4-fluorophenyl-[4-fluoro-4-[[(5-methylpyrimidin-2-ylmethyl)amino]methyl]piperidin- 1-yl]methanone), preferentially activates 5-HT1A Receptors in cortical regions and exhibits potent, rapidacting and sustained antidepressant-like and procognitive properties in animal models. Here the background has been reviewed that led to the discovery of the class of 1-(1-benzoylpiperidin-4- yl)methanamine derivatives, including NLX-101, as well as recent advances in discovery of novel 5-HT1A Receptor biased agonists, notably aryloxyethyl derivatives of 1‑(1-benzoylpiperidin-4yl)methanamine which show promising pharmacological activity both in vitro and in vivo. Overall, the results suggest that opportunities exist for innovative drug discovery of selective 5-HT1A Receptor biased agonists that may open new avenues for the treatment of CNS disorders involving dysfunction of serotonergic neurotransmission.
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activity of serotonin 5 ht1a Receptor biased agonists in rat anxiolytic and antidepressant like properties
ACS Chemical Neuroscience, 2018Co-Authors: Magdalena Jastrzebskawiesek, Mark A Varney, Anna Partyka, Joanna Rychtyk, Marcin Kolaczkowski, Joanna śniecikowska, Anna Wesolowska, Adrian NewmantancrediAbstract:Although serotonin 5-HT1A Receptors constitute attractive therapeutic targets, there is a lack of potential clinical candidates that have a high degree of selectivity and full agonist efficacy. Recently, novel 5-HT1A Receptor "biased agonists" F15599 (also known as NLX-101) and F13714 have been reported that exhibit distinctive properties for in vitro signaling, neurochemical, electrophysiological effects, and in brain imaging. The present study characterized their effects in rat models of anxiety (elevated plus-maze, EPM, and Vogel tests), in depressive-like behavior (forced swim test), and on the induction of the three serotonergic behaviors (forepaw treading, flat body posture, and lower lip retraction). The prototypical 5-HT1A Receptor ligands (±)8-OH-DPAT and buspirone were tested as comparators. In the elevated plus-maze, F15599, F13714, and (±)8-OH-DPAT dose-dependently increased the amount and percentage of time spent in the open arms with minimal effective doses (MED) of 5 mg/kg p.o., 2.5 mg/kg p.o. and 1.25 mg/kg s.c., respectively. The effects of the three agonists were abolished by pretreatment with the selective 5-HT1A Receptor antagonist, WAY100635 (0.63 mg/kg s.c.). Buspirone did not show significant activity in the EPM. In contrast, in the Vogel test only buspirone was active, significantly increasing the number of licks and shocks accepted (active dose: 1.25 mg/kg s.c.). However, WAY100635 failed to reverse the effects of buspirone in this test, suggesting that they were not 5-HT1A Receptor-mediated. In the forced swim test, F15599, F13714, and (±)8-OH-DPAT were potently active, abolishing immobility (MED: 0.63 mg/kg p.o., 0.63 mg/kg p.o. and 0.16 mg/kg s.c., respectively). Buspirone was not active. In measures of serotonergic behavior, F13714 and (±)8-OH-DPAT robustly elicited all three signs of serotonergic behaviors, whereas F15599 and buspirone elicited only lower-lip retraction. Taken together, these observations highlight the distinct profiles of activity of 5-HT1A agonists and suggest that the novel biased agonist F15599 combines pronounced activity in a test of anxiety (elevated plus-maze) with potent antidepressant-like effects and low propensity to induce serotonergic behaviors. These data suggest that selective biased agonists could constitute promising pharmacotherapeutics for mood disorders.
Mark A Varney - One of the best experts on this subject based on the ideXlab platform.
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enhanced aggressive phenotype of tph2 knockout rats is associated with diminished 5 ht1a Receptor sensitivity
Neuropharmacology, 2019Co-Authors: Deborah G A Peeters, Adrian Newmantancredi, S.f. De ,boer, Anneke Terneusen, Mark A Varney, Robbertjan Verkes, Judith R HombergAbstract:Brain serotonin (5-HT) plays a key role in aggressive behaviours and related psychopathologies, but its precise mechanism of action remains elusive. Genetic animal models may provide a tool to elucidate the relationship between aggression and serotonin. The present study showed that tryptophan hydroxylase 2 (Tph2) knockout (KO) rats, which exhibit profoundly diminished extracellular serotonin levels, display increased aggressiveness compared to their Tph2 wildtype (WT) counterparts. However, the level of aggression in Tph2 KO rats did not equal that of feral wild type Groningen (WTG) rats. To investigate whether enhanced 5-HT1A Receptor functionality may be present in Tph2 KO rats, we tested the acute anti-aggressive potency of the highly selective 5-HT1A Receptor full agonist NLX-112 (a.k.a. befiradol or F13640). Data show that compared to Tph2 WT and WTG rats, the NLX-112 dose-effect curve was shifted to the right in Tph2 KO animals. These results suggest that, unlike previous reports in Tph2 KO mice, Tph2 KO rats have a decreased 5-HT1A Receptor sensitivity compared to both Tph2 WT and WTG animals.
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activity of serotonin 5 ht1a Receptor biased agonists in rat anxiolytic and antidepressant like properties
ACS Chemical Neuroscience, 2018Co-Authors: Magdalena Jastrzebskawiesek, Mark A Varney, Anna Partyka, Joanna Rychtyk, Marcin Kolaczkowski, Joanna śniecikowska, Anna Wesolowska, Adrian NewmantancrediAbstract:Although serotonin 5-HT1A Receptors constitute attractive therapeutic targets, there is a lack of potential clinical candidates that have a high degree of selectivity and full agonist efficacy. Recently, novel 5-HT1A Receptor "biased agonists" F15599 (also known as NLX-101) and F13714 have been reported that exhibit distinctive properties for in vitro signaling, neurochemical, electrophysiological effects, and in brain imaging. The present study characterized their effects in rat models of anxiety (elevated plus-maze, EPM, and Vogel tests), in depressive-like behavior (forced swim test), and on the induction of the three serotonergic behaviors (forepaw treading, flat body posture, and lower lip retraction). The prototypical 5-HT1A Receptor ligands (±)8-OH-DPAT and buspirone were tested as comparators. In the elevated plus-maze, F15599, F13714, and (±)8-OH-DPAT dose-dependently increased the amount and percentage of time spent in the open arms with minimal effective doses (MED) of 5 mg/kg p.o., 2.5 mg/kg p.o. and 1.25 mg/kg s.c., respectively. The effects of the three agonists were abolished by pretreatment with the selective 5-HT1A Receptor antagonist, WAY100635 (0.63 mg/kg s.c.). Buspirone did not show significant activity in the EPM. In contrast, in the Vogel test only buspirone was active, significantly increasing the number of licks and shocks accepted (active dose: 1.25 mg/kg s.c.). However, WAY100635 failed to reverse the effects of buspirone in this test, suggesting that they were not 5-HT1A Receptor-mediated. In the forced swim test, F15599, F13714, and (±)8-OH-DPAT were potently active, abolishing immobility (MED: 0.63 mg/kg p.o., 0.63 mg/kg p.o. and 0.16 mg/kg s.c., respectively). Buspirone was not active. In measures of serotonergic behavior, F13714 and (±)8-OH-DPAT robustly elicited all three signs of serotonergic behaviors, whereas F15599 and buspirone elicited only lower-lip retraction. Taken together, these observations highlight the distinct profiles of activity of 5-HT1A agonists and suggest that the novel biased agonist F15599 combines pronounced activity in a test of anxiety (elevated plus-maze) with potent antidepressant-like effects and low propensity to induce serotonergic behaviors. These data suggest that selective biased agonists could constitute promising pharmacotherapeutics for mood disorders.
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Activity of Serotonin 5‑HT1A Receptor Biased Agonists in Rat: Anxiolytic and Antidepressant-like properties
2017Co-Authors: Magdalena Jastrzębska-więsek, Mark A Varney, Anna Partyka, Anna Wesołowska, Joanna Rychtyk, Joanna Śniecikowska, Marcin Kołaczkowski, Adrian Newman-tancrediAbstract:Although serotonin 5-HT1A Receptors constitute attractive therapeutic targets, there is a lack of potential clinical candidates that have a high degree of selectivity and full agonist efficacy. Recently, novel 5-HT1A Receptor “biased agonists” F15599 (also known as NLX-101) and F13714 have been reported that exhibit distinctive properties for in vitro signaling, neurochemical, electrophysiological effects, and in brain imaging. The present study characterized their effects in rat models of anxiety (elevated plus-maze, EPM, and Vogel tests), in depressive-like behavior (forced swim test), and on the induction of the three serotonergic behaviors (forepaw treading, flat body posture, and lower lip retraction). The prototypical 5-HT1A Receptor ligands (±)8-OH-DPAT and buspirone were tested as comparators. In the elevated plus-maze, F15599, F13714, and (±)8-OH-DPAT dose-dependently increased the amount and percentage of time spent in the open arms with minimal effective doses (MED) of 5 mg/kg p.o., 2.5 mg/kg p.o. and 1.25 mg/kg s.c., respectively. The effects of the three agonists were abolished by pretreatment with the selective 5-HT1A Receptor antagonist, WAY100635 (0.63 mg/kg s.c.). Buspirone did not show significant activity in the EPM. In contrast, in the Vogel test only buspirone was active, significantly increasing the number of licks and shocks accepted (active dose: 1.25 mg/kg s.c.). However, WAY100635 failed to reverse the effects of buspirone in this test, suggesting that they were not 5-HT1A Receptor-mediated. In the forced swim test, F15599, F13714, and (±)8-OH-DPAT were potently active, abolishing immobility (MED: 0.63 mg/kg p.o., 0.63 mg/kg p.o. and 0.16 mg/kg s.c., respectively). Buspirone was not active. In measures of serotonergic behavior, F13714 and (±)8-OH-DPAT robustly elicited all three signs of serotonergic behaviors, whereas F15599 and buspirone elicited only lower-lip retraction. Taken together, these observations highlight the distinct profiles of activity of 5-HT1A agonists and suggest that the novel biased agonist F15599 combines pronounced activity in a test of anxiety (elevated plus-maze) with potent antidepressant-like effects and low propensity to induce serotonergic behaviors. These data suggest that selective biased agonists could constitute promising pharmacotherapeutics for mood disorders
Anthony E Kline - One of the best experts on this subject based on the ideXlab platform.
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the therapeutic efficacy conferred by the 5 ht1a Receptor agonist 8 hydroxy 2 di n propylamino tetralin 8 oh dpat after experimental traumatic brain injury is not mediated by concomitant hypothermia
Journal of Neurotrauma, 2004Co-Authors: Anthony E Kline, Jaime L Massucci, Edward C Dixon, Ross Zafonte, Bryan D BolingerAbstract:We recently reported that the 5-HT1A Receptor agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) attenuated traumatic brain injury (TBI)-induced cognitive deficits and histopathology. Howev...
