Neuroscience researcher (over 30 years' experience), Co-Founder and CEO of a bioscience company, Neurolixis, developing clinical-stage drugs for treatment of movement disorders and Autism Spectrum Disorders. Previously Director of Neurobiology at Pierre Fabre, identifying novel antipsychotics, antidepressants and analgesic drug candidates. Prior to Pierre Fabre, investigated signal transduction of monoamine receptors at the Servier Research Institute. Published over 200 articles in peer-reviewed journals and co-inventor on a dozen patents. Serves as European Councilor for the International Society for Serotonin Research. Principal current focus is the development of the first-in-class serotonergic 'biased agonists' befiradol (NLX-112), NLX-101 (F15599) and NLX-204. Previously characterized several approved drugs, including milnacipran (Savella ®), piribedil (Trivastal ®), agomelatine (Valdoxan ®) and levomilnacipran (Fetzima ®). Specialties: neuropharmacology, drug discovery, target validation, early drug development. Particular interest in 'biased agonism' (a.k.a. 'functional selectivity').
Objectives NLX-112 (befiradol, F13640) is a selective serotonin 5-HT1A receptor agonist. Although... more Objectives NLX-112 (befiradol, F13640) is a selective serotonin 5-HT1A receptor agonist. Although it has been tested in vivo, little has been reported on its in vitro signal transduction profile. Methods NLX-112 was tested on G-protein activation, inhibition of adenylyl cyclase, ERK1/2 phosphorylation (pERK) and receptor internalization in recombinant cell lines. NLX-112 was also tested on G-protein activation in rat hippocampal membranes. Gα subunit mRNA expression in cell lines and rat brain tissue was quantified by quantitative PCR. Key findings For all signalling measures, NLX-112 exhibited agonist efficacy greater than for reference compounds ((±)8-OH-DPAT or buspirone), but similar to the endogenous agonist, serotonin, and was more potent for pERK than other responses. In rat hippocampal membranes, NLX-112 stimulated ‘total G-proteins' but, unlike (±)8-OH-DPAT and buspirone, was more potent for Gαo activation. Cell lines predominantly expressed Gαi1 and Gαi2 mRNA, with low...
Purpose The serotonin-1A (5-HT 1A) receptor is implicated in the pathophysiology of major neurops... more Purpose The serotonin-1A (5-HT 1A) receptor is implicated in the pathophysiology of major neuropsychiatric disorders. Thus, the functional imaging of 5-HT 1A receptors by positron emission tomography (PET) may contribute to the understanding of its role in ...
Summary "Atypical" antipsychotics are antagonists at serotonin 5-HT2A and dopamine d2 r... more Summary "Atypical" antipsychotics are antagonists at serotonin 5-HT2A and dopamine d2 receptors. However, their effects on negative symptoms and cognitive deficits remain modest and they disrupt metabolic function. Recent drugs, such as aripiprazole, perospirone, bifeprunox, lurasidone and cariprazine act as D2 recep- tor antagonists (or partial agonists) combined with 5-HT1A receptor activation. The latter prevents extrapy - ramidal symptoms, favors prefrontal cortex dopaminergic neurotransmission, has a beneficial influence on mood and opposes cognitive deficits. Further, recent drugs exhibit little interaction at sites associated with side-effects such as metabolic disorders or autonomic disturbance. However, these drugs differ in their bal- ance of 5-HT1A/D2 receptor properties and this is likely to translate to distinct therapeutic profiles. 5-HT1A receptors/ d2 receptors/ antipsychotic/ schizophrenia
Rationale The prevalence of depression is ever-increasing throughout the population. However, ava... more Rationale The prevalence of depression is ever-increasing throughout the population. However, available treatments are ineffective in around one-third of patients and there is a need for more effective and safer drugs. Objectives The antidepressant-like and procognitive effects of the “biased agonists” F15599 (also known as NLX-101) which preferentially targets postsynaptic 5-HT1A receptors and F13714, which targets 5-HT1A autoreceptors, were investigated in mice. Methods Antidepressant-like properties of the compounds and their effect on cognitive functions were assessed using the forced swim test (FST) and the novel object recognition (NOR), respectively. Next, we induced a depressive-like state by an unpredictable chronic mild stress (UCMS) procedure to test the compounds’ activity in the depression model, followed by measures of sucrose preference, FST, and locomotor activity. Levels of phosphorylated cyclic AMP response element-binding protein (p-CREB) and phosphorylated extrac...
For this issue, Luc Zimmer, professor of pharmacology and chair of the Neuropsychopharmacology Co... more For this issue, Luc Zimmer, professor of pharmacology and chair of the Neuropsychopharmacology Committee of the French Society of Pharmacology and Therapeutics (SFPT), talked with Adrian Newman-Tancredi, neuropharmacologist, co-founder and CEO of a biopharmaceutical company developing clinical-stage central nervous system drugs. They address through experiences the particularities of research in neuropsychopharmacology in the pharmaceutical industry. The evolution of drug discovery strategy is also discussed, as well as the reasons for the contrasting landscape of research for new molecules for psychiatry.
The serotonin 5-HT1A receptor has attracted wide attention as a target for treatment of psychiatr... more The serotonin 5-HT1A receptor has attracted wide attention as a target for treatment of psychiatric disorders. Although this receptor is important in the pharmacological mechanisms of action of new-generation antipsychotics, its characterization remains incomplete. Studies based on in vitro molecular imaging on brain tissue by autoradiography, and more recently in vivo PET imaging, have not yielded clear results, in particular due to the limitations of current 5-HT1A radiotracers, which lack specificity and/or bind to all 5-HT1A receptors, regardless of their functional status. The new concept of PET neuroimaging of functionally active G-protein-coupled receptors makes it possible to revisit PET brain exploration by enabling new research paradigms. For the 5-HT1A receptor it is now possible to use [18F]-F13640, a 5-HT1A receptor radioligand with high efficacy agonist properties, to specifically visualize and quantify functionally active receptors, and to relate this information to s...
Peak-dose dyskinesia is associated with the dramatic increase in striatal dopamine levels that fo... more Peak-dose dyskinesia is associated with the dramatic increase in striatal dopamine levels that follows l-DOPA administration. The ‘false neurotransmitter’ hypothesis postulates that the latter is likely due to an aberrant processing of l-DOPA by serotonergic neurons. In keeping with this hypothesis, two highly selective ‘biased agonists’ of 5-HT1A receptors—namely F13714 and F15599 (NLX-101)—were recently shown to exhibit exceptionally potent anti-dyskinetic activity without impairing l-DOPA therapeutic properties despite their differential targeting of 5-HT1A receptor sub-populations. In this study, we investigated whether these two compounds dampened peak l-DOPA-induced dopamine microdialysate levels in the striatum of hemi-parkinsonian rats. Acute administration of either F13714 (0.04 and 0.16 mg/kg i.p.) or F15599 (0.16 and 0.64 mg/kg, i.p.) blunted l-DOPA (2 mg/kg)-induced increases in dopamine microdialysate levels in the denervated striatum (following unilateral injection of 6-OHDA into the medial forebrain bundle). No significant changes were observed on the intact side of the brain. Concurrently, both drugs profoundly reduced striatal serotonin levels on both sides of the brain. In addition, F13714 and F15599, in the presence of l-DOPA, produced a dose-dependent increase in glutamate levels, but this effect was restricted to later time points. These finding support the interpretation that F13714 and F15599 mediate their anti-dyskinetic effects by blunting of the peak in dopamine levels via activation of somatodendritic serotonin 5-HT1A receptors and the consequent inhibition of serotonergic neurons. This study adds to the growing body of evidence supporting the development of a potent 5-HT1A receptor agonist for treatment of peak-dose dyskinesia.
ABSTRACT Recently, the biased and highly selective 5‐HT1A agonists, NLX‐112, F13714 and F15599, h... more ABSTRACT Recently, the biased and highly selective 5‐HT1A agonists, NLX‐112, F13714 and F15599, have been shown to alleviate dyskinesia in rodent and primate models of Parkinson's disease, while marginally interfering with antiparkinsonian effects of levodopa. To provide more detailed information on the processes underlying the alleviation of dyskinesia, we have here investigated changes in the spectral contents of local field potentials in cortico‐basal ganglia‐thalamic circuits following treatment with this novel group of 5‐HT1A agonists or the prototypical agonist, 8‐OH‐DPAT. Dyskinetic symptoms were consistently associated with 80Hz oscillations, which were efficaciously suppressed by all 5‐HT1A agonists and reappeared upon co‐administration of the antagonist, WAY100635. At the same time, the peak‐frequency of fast 130Hz gamma oscillations and their cross‐frequency coupling to low‐frequency delta oscillations were modified to a different extent by each of the 5‐HT1A agonists. These findings suggest that the common antidyskinetic effects of these drugs may be chiefly attributable to a reversal of the brain state characterized by 80Hz gamma oscillations, whereas the differential effects on fast gamma oscillations may reflect differences in pharmacological properties that might be of potential relevance for non‐motor symptoms. HIGHLIGHTSSystems‐level neurophysiological states reveal pharmacological profiles.5‐HT1A receptor biased agonists are antidyskinetic and reduce 80Hz oscillations.5‐HT1A receptor biased agonists show differential effects on fast gamma oscillations.
Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology, 2018
In neuropharmacology, the recent concept of 'biased agonism' denotes the capacity of cert... more In neuropharmacology, the recent concept of 'biased agonism' denotes the capacity of certain agonists to target-specific intracellular pathways of a given receptor in specific brain areas. In the context of serotonin pharmacotherapy, 5-HT receptor-biased agonists could be of great interest in several neuropsychiatric disorders. The aim of this study was to determine whether biased agonists could be differentiated in terms of regional targeting by use of simultaneous functional magnetic resonance imaging (fMRI) and positron emission tomography (PET) brain imaging. We compared two 5-HT-biased agonists, NLX-112 and NLX-101, injected at three different doses in anaesthetised cats (n = 4). PET imaging was acquired for 90 min after bolus administration followed by constant infusion of the 5-HT radiotracer, [F]MPPF. Drug occupancy was evaluated after injection at 50 min and BOLD fMRI was simultaneously acquired to evaluate subsequent brain activation patterns. 5-HT receptor occupa...
Serotonin 1A receptors are known to play an important role in many psychiatric and neurodegenerat... more Serotonin 1A receptors are known to play an important role in many psychiatric and neurodegenerative disorders. Currently, all available 5-HT receptor PET radiopharmaceuticals that are radiolabeled with fluorine-18 are antagonists. As agonists bind preferentially to the high-affinity state of receptors, it would be of great interest to develop agonist radioligands which could provide a measure of the functional 5-HT receptors in pathophysiological processes. The 5-HT receptor agonist candidates we recently proposed had promising in vitro properties but were not optimal in terms of PET imaging. F13640, a.k.a befiradol or NLX-112, is a 5-HT receptor agonist with a high affinity (Ki = 1 nM) and a high selectivity that would be suitable for a potential PET radiopharmaceutical. With propose here the first preclinical evaluation of F-F13640. F-F13640's nitro-precursor was synthesized and radiolabeled via a fluoro-nucleophilic substitution. Its radiopharmacological characterization inc...
BACKGROUND AND PURPOSE NLX-112 (a.k.a. befiradol, F13640) is a drug candidate intended for the tr... more BACKGROUND AND PURPOSE NLX-112 (a.k.a. befiradol, F13640) is a drug candidate intended for the treatment of l-DOPA-induced dyskinesia. It is a highly selective serotonin 5-HT1A receptor full agonist which has been previously tested in a variety of models of CNS effects including analgesic activity in rat. Its activity in mouse models of pain has not been previously investigated. EXPERIMENTAL APPROACH The activity of NLX-112 was tested in mouse models of acute pain (hot plate), tonic pain (intraplantar formalin test), in the oxaliplatin-induced neuropathic pain model of chemotherapy-induced peripheral neuropathy and in the streptozotocin (STZ)-induced model of painful diabetic neuropathy. KEY RESULTS The main findings indicate that (i) NLX-112 was markedly active in the formalin test with potent reduction of paw licking in both phases of the test (minimal effective dose (MED) 0.5 mg/kg i.p. and p.o. in acute phase, and 0.1 mg/kg i.p. and 1 mg/kg p.o. in late phase). The effects of NLX-112 in this test were completely abolished by the selective 5-HT1A receptor antagonist, WAY100635; (ii) NLX-112 was active in the hot plate test and in the oxaliplatin-induced neuropathic pain model of chemotherapy-induced peripheral neuropathy, but at markedly higher doses (MED 2.5 mg/kg i.p.); (iii) NLX-112 was least active in the STZ-induced model of painful diabetic neuropathy (MED 5 mg/kg i.p.); (iv) NLX-112 did not affect locomotor activity. CONCLUSIONS AND IMPLICATIONS NLX-112 may have significant potential for treatment of tonic pain but may be less promising as a candidate for treatment of chemotherapy-induced or diabetic neuropathic pain.
The international journal of neuropsychopharmacology / official scientific journal of the Collegium Internationale Neuropsychopharmacologicum (CINP), Jan 8, 2016
In vivo mapping by positron emission tomography (PET) of the serotonin 1A (5-HT1A) receptors has ... more In vivo mapping by positron emission tomography (PET) of the serotonin 1A (5-HT1A) receptors has been hindered by the lack of suitable agonist PET probes. (18)F-labeled F13714 is a recently-developed biased agonist PET probe that preferentially targets subpopulations of 5-HT1A receptors in their 'active state', but its brain labeling pattern in non-human primate has not been described. In addition, a potential confound in the translatability of PET data between non-human animal and human arise from the use of anesthetics which may modify the binding profiles of target receptors. PET scans were conducted in a cohort of common marmosets (n=4) using the 5-HT1A receptor biased agonist radiotracer, (18)F-F13714, compared with a well-characterized (18)F-labeled antagonist radiotracer, (18)F-MPPF. Experiments on each animal were performed under both consciousness and isoflurane-anesthesia conditions. (18)F-F13714 binding distribution in marmosets by PET differs markedly from that o...
The serotonin (5-HT) deficiency hypothesis of aggression is being seriously challenged by pharmac... more The serotonin (5-HT) deficiency hypothesis of aggression is being seriously challenged by pharmacological data showing robust anti-aggressive effects of 5-HT1A receptor agonists in dose ranges that concomitantly inhibit 5-HT neurotransmission. Hence, an adequate interpretation of the role of 5-HT activity in regulating aggression depends on elucidating the predominant site of action, i.e., raphe presynaptic autoreceptors versus forebrain postsynaptic heteroreceptors, of these 5-HT1A receptor agonists. The present experiments investigated the anti-aggressive properties of the selective 5-HT1A receptor agonists F15599 that preferentially target postsynaptic 5-HT1A heteroreceptors in the frontal cortex and F13714 that more preferentially activates raphe somatodendritic 5-HT1A autoreceptors. Both 'biased' agonists were acutely administered intraperitoneally in aggressive resident male WTG rats confronting an intruder. Systemic administration of F15599 and F13714 exerted very pot...
Objectives NLX-112 (befiradol, F13640) is a selective serotonin 5-HT1A receptor agonist. Although... more Objectives NLX-112 (befiradol, F13640) is a selective serotonin 5-HT1A receptor agonist. Although it has been tested in vivo, little has been reported on its in vitro signal transduction profile. Methods NLX-112 was tested on G-protein activation, inhibition of adenylyl cyclase, ERK1/2 phosphorylation (pERK) and receptor internalization in recombinant cell lines. NLX-112 was also tested on G-protein activation in rat hippocampal membranes. Gα subunit mRNA expression in cell lines and rat brain tissue was quantified by quantitative PCR. Key findings For all signalling measures, NLX-112 exhibited agonist efficacy greater than for reference compounds ((±)8-OH-DPAT or buspirone), but similar to the endogenous agonist, serotonin, and was more potent for pERK than other responses. In rat hippocampal membranes, NLX-112 stimulated ‘total G-proteins' but, unlike (±)8-OH-DPAT and buspirone, was more potent for Gαo activation. Cell lines predominantly expressed Gαi1 and Gαi2 mRNA, with low...
Purpose The serotonin-1A (5-HT 1A) receptor is implicated in the pathophysiology of major neurops... more Purpose The serotonin-1A (5-HT 1A) receptor is implicated in the pathophysiology of major neuropsychiatric disorders. Thus, the functional imaging of 5-HT 1A receptors by positron emission tomography (PET) may contribute to the understanding of its role in ...
Summary "Atypical" antipsychotics are antagonists at serotonin 5-HT2A and dopamine d2 r... more Summary "Atypical" antipsychotics are antagonists at serotonin 5-HT2A and dopamine d2 receptors. However, their effects on negative symptoms and cognitive deficits remain modest and they disrupt metabolic function. Recent drugs, such as aripiprazole, perospirone, bifeprunox, lurasidone and cariprazine act as D2 recep- tor antagonists (or partial agonists) combined with 5-HT1A receptor activation. The latter prevents extrapy - ramidal symptoms, favors prefrontal cortex dopaminergic neurotransmission, has a beneficial influence on mood and opposes cognitive deficits. Further, recent drugs exhibit little interaction at sites associated with side-effects such as metabolic disorders or autonomic disturbance. However, these drugs differ in their bal- ance of 5-HT1A/D2 receptor properties and this is likely to translate to distinct therapeutic profiles. 5-HT1A receptors/ d2 receptors/ antipsychotic/ schizophrenia
Rationale The prevalence of depression is ever-increasing throughout the population. However, ava... more Rationale The prevalence of depression is ever-increasing throughout the population. However, available treatments are ineffective in around one-third of patients and there is a need for more effective and safer drugs. Objectives The antidepressant-like and procognitive effects of the “biased agonists” F15599 (also known as NLX-101) which preferentially targets postsynaptic 5-HT1A receptors and F13714, which targets 5-HT1A autoreceptors, were investigated in mice. Methods Antidepressant-like properties of the compounds and their effect on cognitive functions were assessed using the forced swim test (FST) and the novel object recognition (NOR), respectively. Next, we induced a depressive-like state by an unpredictable chronic mild stress (UCMS) procedure to test the compounds’ activity in the depression model, followed by measures of sucrose preference, FST, and locomotor activity. Levels of phosphorylated cyclic AMP response element-binding protein (p-CREB) and phosphorylated extrac...
For this issue, Luc Zimmer, professor of pharmacology and chair of the Neuropsychopharmacology Co... more For this issue, Luc Zimmer, professor of pharmacology and chair of the Neuropsychopharmacology Committee of the French Society of Pharmacology and Therapeutics (SFPT), talked with Adrian Newman-Tancredi, neuropharmacologist, co-founder and CEO of a biopharmaceutical company developing clinical-stage central nervous system drugs. They address through experiences the particularities of research in neuropsychopharmacology in the pharmaceutical industry. The evolution of drug discovery strategy is also discussed, as well as the reasons for the contrasting landscape of research for new molecules for psychiatry.
The serotonin 5-HT1A receptor has attracted wide attention as a target for treatment of psychiatr... more The serotonin 5-HT1A receptor has attracted wide attention as a target for treatment of psychiatric disorders. Although this receptor is important in the pharmacological mechanisms of action of new-generation antipsychotics, its characterization remains incomplete. Studies based on in vitro molecular imaging on brain tissue by autoradiography, and more recently in vivo PET imaging, have not yielded clear results, in particular due to the limitations of current 5-HT1A radiotracers, which lack specificity and/or bind to all 5-HT1A receptors, regardless of their functional status. The new concept of PET neuroimaging of functionally active G-protein-coupled receptors makes it possible to revisit PET brain exploration by enabling new research paradigms. For the 5-HT1A receptor it is now possible to use [18F]-F13640, a 5-HT1A receptor radioligand with high efficacy agonist properties, to specifically visualize and quantify functionally active receptors, and to relate this information to s...
Peak-dose dyskinesia is associated with the dramatic increase in striatal dopamine levels that fo... more Peak-dose dyskinesia is associated with the dramatic increase in striatal dopamine levels that follows l-DOPA administration. The ‘false neurotransmitter’ hypothesis postulates that the latter is likely due to an aberrant processing of l-DOPA by serotonergic neurons. In keeping with this hypothesis, two highly selective ‘biased agonists’ of 5-HT1A receptors—namely F13714 and F15599 (NLX-101)—were recently shown to exhibit exceptionally potent anti-dyskinetic activity without impairing l-DOPA therapeutic properties despite their differential targeting of 5-HT1A receptor sub-populations. In this study, we investigated whether these two compounds dampened peak l-DOPA-induced dopamine microdialysate levels in the striatum of hemi-parkinsonian rats. Acute administration of either F13714 (0.04 and 0.16 mg/kg i.p.) or F15599 (0.16 and 0.64 mg/kg, i.p.) blunted l-DOPA (2 mg/kg)-induced increases in dopamine microdialysate levels in the denervated striatum (following unilateral injection of 6-OHDA into the medial forebrain bundle). No significant changes were observed on the intact side of the brain. Concurrently, both drugs profoundly reduced striatal serotonin levels on both sides of the brain. In addition, F13714 and F15599, in the presence of l-DOPA, produced a dose-dependent increase in glutamate levels, but this effect was restricted to later time points. These finding support the interpretation that F13714 and F15599 mediate their anti-dyskinetic effects by blunting of the peak in dopamine levels via activation of somatodendritic serotonin 5-HT1A receptors and the consequent inhibition of serotonergic neurons. This study adds to the growing body of evidence supporting the development of a potent 5-HT1A receptor agonist for treatment of peak-dose dyskinesia.
ABSTRACT Recently, the biased and highly selective 5‐HT1A agonists, NLX‐112, F13714 and F15599, h... more ABSTRACT Recently, the biased and highly selective 5‐HT1A agonists, NLX‐112, F13714 and F15599, have been shown to alleviate dyskinesia in rodent and primate models of Parkinson's disease, while marginally interfering with antiparkinsonian effects of levodopa. To provide more detailed information on the processes underlying the alleviation of dyskinesia, we have here investigated changes in the spectral contents of local field potentials in cortico‐basal ganglia‐thalamic circuits following treatment with this novel group of 5‐HT1A agonists or the prototypical agonist, 8‐OH‐DPAT. Dyskinetic symptoms were consistently associated with 80Hz oscillations, which were efficaciously suppressed by all 5‐HT1A agonists and reappeared upon co‐administration of the antagonist, WAY100635. At the same time, the peak‐frequency of fast 130Hz gamma oscillations and their cross‐frequency coupling to low‐frequency delta oscillations were modified to a different extent by each of the 5‐HT1A agonists. These findings suggest that the common antidyskinetic effects of these drugs may be chiefly attributable to a reversal of the brain state characterized by 80Hz gamma oscillations, whereas the differential effects on fast gamma oscillations may reflect differences in pharmacological properties that might be of potential relevance for non‐motor symptoms. HIGHLIGHTSSystems‐level neurophysiological states reveal pharmacological profiles.5‐HT1A receptor biased agonists are antidyskinetic and reduce 80Hz oscillations.5‐HT1A receptor biased agonists show differential effects on fast gamma oscillations.
Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology, 2018
In neuropharmacology, the recent concept of 'biased agonism' denotes the capacity of cert... more In neuropharmacology, the recent concept of 'biased agonism' denotes the capacity of certain agonists to target-specific intracellular pathways of a given receptor in specific brain areas. In the context of serotonin pharmacotherapy, 5-HT receptor-biased agonists could be of great interest in several neuropsychiatric disorders. The aim of this study was to determine whether biased agonists could be differentiated in terms of regional targeting by use of simultaneous functional magnetic resonance imaging (fMRI) and positron emission tomography (PET) brain imaging. We compared two 5-HT-biased agonists, NLX-112 and NLX-101, injected at three different doses in anaesthetised cats (n = 4). PET imaging was acquired for 90 min after bolus administration followed by constant infusion of the 5-HT radiotracer, [F]MPPF. Drug occupancy was evaluated after injection at 50 min and BOLD fMRI was simultaneously acquired to evaluate subsequent brain activation patterns. 5-HT receptor occupa...
Serotonin 1A receptors are known to play an important role in many psychiatric and neurodegenerat... more Serotonin 1A receptors are known to play an important role in many psychiatric and neurodegenerative disorders. Currently, all available 5-HT receptor PET radiopharmaceuticals that are radiolabeled with fluorine-18 are antagonists. As agonists bind preferentially to the high-affinity state of receptors, it would be of great interest to develop agonist radioligands which could provide a measure of the functional 5-HT receptors in pathophysiological processes. The 5-HT receptor agonist candidates we recently proposed had promising in vitro properties but were not optimal in terms of PET imaging. F13640, a.k.a befiradol or NLX-112, is a 5-HT receptor agonist with a high affinity (Ki = 1 nM) and a high selectivity that would be suitable for a potential PET radiopharmaceutical. With propose here the first preclinical evaluation of F-F13640. F-F13640's nitro-precursor was synthesized and radiolabeled via a fluoro-nucleophilic substitution. Its radiopharmacological characterization inc...
BACKGROUND AND PURPOSE NLX-112 (a.k.a. befiradol, F13640) is a drug candidate intended for the tr... more BACKGROUND AND PURPOSE NLX-112 (a.k.a. befiradol, F13640) is a drug candidate intended for the treatment of l-DOPA-induced dyskinesia. It is a highly selective serotonin 5-HT1A receptor full agonist which has been previously tested in a variety of models of CNS effects including analgesic activity in rat. Its activity in mouse models of pain has not been previously investigated. EXPERIMENTAL APPROACH The activity of NLX-112 was tested in mouse models of acute pain (hot plate), tonic pain (intraplantar formalin test), in the oxaliplatin-induced neuropathic pain model of chemotherapy-induced peripheral neuropathy and in the streptozotocin (STZ)-induced model of painful diabetic neuropathy. KEY RESULTS The main findings indicate that (i) NLX-112 was markedly active in the formalin test with potent reduction of paw licking in both phases of the test (minimal effective dose (MED) 0.5 mg/kg i.p. and p.o. in acute phase, and 0.1 mg/kg i.p. and 1 mg/kg p.o. in late phase). The effects of NLX-112 in this test were completely abolished by the selective 5-HT1A receptor antagonist, WAY100635; (ii) NLX-112 was active in the hot plate test and in the oxaliplatin-induced neuropathic pain model of chemotherapy-induced peripheral neuropathy, but at markedly higher doses (MED 2.5 mg/kg i.p.); (iii) NLX-112 was least active in the STZ-induced model of painful diabetic neuropathy (MED 5 mg/kg i.p.); (iv) NLX-112 did not affect locomotor activity. CONCLUSIONS AND IMPLICATIONS NLX-112 may have significant potential for treatment of tonic pain but may be less promising as a candidate for treatment of chemotherapy-induced or diabetic neuropathic pain.
The international journal of neuropsychopharmacology / official scientific journal of the Collegium Internationale Neuropsychopharmacologicum (CINP), Jan 8, 2016
In vivo mapping by positron emission tomography (PET) of the serotonin 1A (5-HT1A) receptors has ... more In vivo mapping by positron emission tomography (PET) of the serotonin 1A (5-HT1A) receptors has been hindered by the lack of suitable agonist PET probes. (18)F-labeled F13714 is a recently-developed biased agonist PET probe that preferentially targets subpopulations of 5-HT1A receptors in their 'active state', but its brain labeling pattern in non-human primate has not been described. In addition, a potential confound in the translatability of PET data between non-human animal and human arise from the use of anesthetics which may modify the binding profiles of target receptors. PET scans were conducted in a cohort of common marmosets (n=4) using the 5-HT1A receptor biased agonist radiotracer, (18)F-F13714, compared with a well-characterized (18)F-labeled antagonist radiotracer, (18)F-MPPF. Experiments on each animal were performed under both consciousness and isoflurane-anesthesia conditions. (18)F-F13714 binding distribution in marmosets by PET differs markedly from that o...
The serotonin (5-HT) deficiency hypothesis of aggression is being seriously challenged by pharmac... more The serotonin (5-HT) deficiency hypothesis of aggression is being seriously challenged by pharmacological data showing robust anti-aggressive effects of 5-HT1A receptor agonists in dose ranges that concomitantly inhibit 5-HT neurotransmission. Hence, an adequate interpretation of the role of 5-HT activity in regulating aggression depends on elucidating the predominant site of action, i.e., raphe presynaptic autoreceptors versus forebrain postsynaptic heteroreceptors, of these 5-HT1A receptor agonists. The present experiments investigated the anti-aggressive properties of the selective 5-HT1A receptor agonists F15599 that preferentially target postsynaptic 5-HT1A heteroreceptors in the frontal cortex and F13714 that more preferentially activates raphe somatodendritic 5-HT1A autoreceptors. Both 'biased' agonists were acutely administered intraperitoneally in aggressive resident male WTG rats confronting an intruder. Systemic administration of F15599 and F13714 exerted very pot...
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