Publications

 

Neurolixis is a science-driven company and places high priority on characterizing its drug development candidates (NLX-112 and NLX-101) in rigorously-conducted pharmacological studies. NLX-112 was previously known as F13640 (befiradol) whereas NLX-101 was previously known as F15599.

For a complete list of publications on NLX-112 and NLX-101, see the PubMed database.

For abstracts (and some free PDFs) of selected publications see the links below.

 

Publications

Neurolixis is a science-driven company and places high priority on characterizing its drug development candidates (NLX-112 and NLX-101) in rigorously-conducted pharmacological studies. The results from these studies are reported in reputable international peer-reviewed neuroscience and pharmacology journals.
Note: NLX-112 was previously known as F13640 (befiradol) and NLX-101 was previously known as F15599.

To see over 40 publications on NLX-112 and NLX-101 see PubMed database (from US National Library of Medicine): complete list of publications

For abstracts of key publications (and some free PDFs of the full articles) see the links below.

 

Selected Publications on NLX-112:

The novel 5-HT1A receptor agonist, NLX-112, reduces L-DOPA-induced abnormal involuntary movements in rat: a chronic administration study with microdialysis measurements.

McCreary AC, Varney MA, Newman-Tancredi A
Neuropharmacology. 2016 Jan 8. pii: S0028-3908(16)30013-2. doi: 10.1016/j.neuropharm.2016.01.013.

 

NLX-112, a novel 5-HT1A receptor agonist for the treatment of L-DOPA-induced dyskinesia: Behavioral and neurochemical profile in rat.

Iderberg H, McCreary AC, Varney MA, Kleven MS, Koek W, Bardin L, Depoortère R, Cenci MA, Newman-Tancredi A
Exp Neurol. 2015 May 30. doi: 10.1016/j.expneurol.2015.05.021

 

In vivo electrophysiological and neurochemical effects of the selective 5-HT1A receptor agonist, F13640, at pre- and post-synaptic 5-HT1A receptors in the rat.

Lladò-Pelfort L, Assié MB, Newman-Tancredi A, Artigas F, Celada P.
Psychopharmacology (Berl). 2012 May;221(2):261-72. Epub 2011 Dec 3.

 

Dual hyperalgesic and analgesic effects of the high-efficacy 5-HT1A agonist F13640: relationship with receptor occupancy and kinetic parameters.

Bardin L, Assié MB, Pélissou M, Royer-Urios I, Newman-Tancredi A, Ribet JP, Sautel F, Koek W, Colpaert FC.
J Pharmacol Exp Ther. 2005 Mar;312(3):1034-42. Epub 2004 Nov 4.    Free PDF  pdf_symbol

 

Selected Publications on NLX-101:

Selective serotonin 5-HT1A receptor biased agonists elicitdistinct brain activation patterns: a pharmacoMRI study (free PDF).

Becker G, Bolbos R, Costes N, Redouté J, Newman-Tancredi A, Zimmer L
Sci Rep. 2016 May 23;6:26633. doi: 10.1038/srep26633.    Free PDF  pdf_symbol

 

Pinpointing brain stem mechanisms responsible for autonomic dysfunction in Rett syndrome: therapeutic perspectives for 5-HT1A agonists

Ana P. Abdala, John Bissonnette, Adrian Newman-Tancredi,
Frontiers in Physiology 5: 205, 2014. doi: 10.3389/fphys.2014.00205   Free PDF  pdf_symbol

 

A selective 5-HT1A receptor agonist improves respiration in a mouse model of Rett syndrome.

Levitt ES, Hunnicutt BJ, Knopp SJ, Williams JT, Bissonnette JM.
J Appl Physiol (1985). 2013 Dec;115(11):1626-33. Epub 2013 Oct 3.

 

Signal transduction and functional selectivity of F15599, a preferential post-synaptic 5-HT1A receptor agonist. 

Newman-Tancredi A, Martel JC, Assié MB, Buritova J, Lauressergues E, Cosi C, Heusler P, BruinsSlot L, Colpaert F, Vacher B, Cussac D.
Br J Pharmacol. 2009 Jan;156(2):338-53. Epub 2009 Jan 12.    Free PDF  pdf_symbol

 

Preferential in vivo action of F15599, a novel 5-HT1A receptor agonist, at postsynaptic 5-HT1A receptors.

Lladó-Pelfort L, Assié MB, Newman-Tancredi A, Artigas F, Celada P.
Br J Pharmacol. 2010 Aug;160(8):1929-40.     Free PDF  pdf_symbol

 

F15599, a preferential post-synaptic 5-HT1A receptor agonist: activity in models of cognition in comparison with reference 5-HT1A receptor agonists.

Depoortère R, Auclair AL, Bardin L, Colpaert FC, Vacher B, Newman-Tancredi A.,
Eur Neuropsychopharmacol. 2010 Sep;20(9):641-54.

 

Biased agonism at serotonin 5-HT1A receptors: preferential postsynaptic activity for improved therapy of CNS disorders.

Newman-Tancredi A,
Neuropsychiatry, April 2011, Vol. 1, No. 2, Pages 149-164.

Signal transduction and functional selectivity of F15599, a preferential post-synaptic 5-HT1A receptor agonist.

Newman-Tancredi A, Martel JC, Assié MB, Buritova J, Lauressergues E, Cosi C, Heusler P, BruinsSlot L, Colpaert F, Vacher B, Cussac D.
Br J Pharmacol. 2009 Jan;156(2):338-53. Epub 2009 Jan 12.

pdf_symbol  Free PDF

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]-GTPgammaS 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]-GTPgammaS binding more potently in frontal cortex than raphe. F15599, unlike 5-HT, more potently and efficaciously stimulated G(alphai) than G(alphao) 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-HT(1A) 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.

A selective 5-HT1A receptor agonist improves respiration in a mouse model of Rett syndrome.

Levitt ES, Hunnicutt BJ, Knopp SJ, Williams JT, Bissonnette JM.
J Appl Physiol (1985). 2013 Dec;115(11):1626-33. Epub 2013 Oct 3.

Rett syndrome is a neurological disorder caused by loss of function mutations in the gene that encodes the DNA binding protein methyl-CpG-binding protein 2 (Mecp2). A prominent feature of the syndrome is disturbances in respiration characterized by frequent apnea and an irregular interbreath cycle. 8-Hydroxy-2-dipropylaminotetralin has been shown to positively modulate these disturbances (Abdala AP, Dutschmann M, Bissonnette JM, Paton JF, Proc Natl Acad Sci USA 107: 18208-18213, 2010), but the mode of action is not understood. Here we show that the selective 5-HT1A biased agonist 3-chloro-4-fluorophenyl-(4-fluoro-4-{[(5-methylpyrimidin-2-ylmethyl)-amino]-methyl}-piperidin-1-yl)-methanone (F15599) decreases apnea and corrects irregularity in both heterozygous Mecp2-deficient female and in Mecp2 null male mice. In whole cell voltage-clamp recordings from dorsal raphe neurons, F15599 potently induced an outward current, which was blocked by barium, reversed at the potassium equilibrium potential, and was antagonized by the 5-HT1a antagonist WAY100135. This is consistent with somatodendritic 5-HT1A receptor-mediated activation of G protein-coupled inwardly rectifying potassium channels (GIRK). In contrast, F15599 did not activate 5-HT1B/D receptors that mediate inhibition of glutamate release from terminals in the nucleus accumbens by a presynaptic mechanism. Thus F15599 activated somatodendritic 5-HT1A autoreceptors, but not axonal 5-HT1B/D receptors. In unanesthetized Mecp2-deficient heterozygous female mice, F15599 reduced apnea in a dose-dependent manner with maximal effect of 74.5 ± 6.9% at 0.1 mg/kg and improved breath irrregularity. Similarly, in Mecp2 null male mice, apnea was reduced by 62 ± 6.6% at 0.25 mg/kg, and breathing became regular. The results indicate respiration is improved with a 5-HT1A agonist that activates GIRK channels without affecting neurotransmitter release.

Preferential in vivo action of F15599, a novel 5-HT1A receptor agonist, at postsynaptic 5-HT1A receptors.

Lladó-Pelfort L, Assié MB, Newman-Tancredi A, Artigas F, Celada P.
Br J Pharmacol. 2010 Aug;160(8):1929-40.

pdf_symbol  Free PDF

BACKGROUND AND PURPOSE: F15599, a novel 5-hydroxytryptamine 5-HT1A receptor agonist with 1000-fold selectivity for 5-HT compared with other monoamine receptors, shows antidepressant and procognitive activity at very low doses in animal models. We examined the in vivo activity of F15599 at somatodendritic autoreceptors and postsynaptic 5-HT1A heteroreceptors.

EXPERIMENTAL APPROACH: In vivo single unit and local field potential recordings and microdialysis in the rat.

KEY RESULTS: F15599 increased the discharge rate of pyramidal neurones in medial prefrontal cortex (mPFC) from 0.2 microg/kg i.v and reduced that of dorsal raphe 5-hydroxytryptaminergic neurones at doses >10-fold higher (minimal effective dose 8.2 microg/kg i.v.). Both effects were reversed by the 5-HT1A antagonist (+/-)WAY100635. F15599 did not alter low frequency oscillations (approximately 1 Hz) in mPFC. In microdialysis studies, F15599 increased dopamine output in mPFC (an effect dependent on the activation of postsynaptic 5-HT1A receptors) with an ED50 of 30 microg/kg i.p., whereas it reduced hippocampal 5-HT release (an effect dependent exclusively on 5-HT1A autoreceptor activation) with an ED50 of 240 microg/kg i.p. Likewise, application of F15599 by reverse dialysis in mPFC increased dopamine output in a concentration-dependent manner. All neurochemical responses to F15599 were prevented by administration of (+/-)WAY100635.

CONCLUSIONS AND IMPLICATIONS: These results indicate that systemic administration of F15599 preferentially activates postsynaptic 5-HT1A receptors in PFC rather than somatodendritic 5-HT1A autoreceptors. This regional selectivity distinguishes F15599 from previously developed 5-HT1A receptor agonists, which preferentially activate somatodendritic 5-HT1A autoreceptors, suggesting that F15599 may be particularly useful in the treatment of depression and of cognitive deficits in schizophrenia.

Dual hyperalgesic and analgesic effects of the high-efficacy 5-HT1A agonist F13640: relationship with receptor occupancy and kinetic parameters.

Bardin L, Assié MB, Pélissou M, Royer-Urios I, Newman-Tancredi A, Ribet JP, Sautel F, Koek W, Colpaert FC.
J Pharmacol Exp Ther. 2005 Mar;312(3):1034-42. Epub 2004 Nov 4.

pdf_symbol  Free PDF

The aim of the present study was to establish the relationship between the plasma and brain concentration-time profiles of F 13640 [(3-chloro-4-fluoro-phenyl)-[4-fluoro-4-{[(5-methyl-pyridin-2-ylmethyl)-amino]-methyl}piperidin-1-yl]methanone, fumaric acid salt] after acute administration and both its hyper- and hypoanalgesic effects in rats. The maximal plasma concentration (Cmax) of F 13640 after i.p. administration of 0.63 mg/kg was obtained at 15 min and decreased to half its maximal value after about 1 h. The amount of F13640 collected by means of in vivo microdialysis in hippocampal dialysates could be measured reliably after 0.63 and 2.5 mg/kg, reached its maximum at about 1 h, and fell to half of its maximal value at about 3 h. 5-Hydroxytryptamine 1A (5-HT1A) receptor occupancy was estimated by ex vivo binding in rat brain sections. F 13640 inhibited [3H]8-hydroxy-2-[di-n-propylamino] tetralin binding ex vivo in rat hippocampus, entorhinal cortex, and frontal cortex (ED50, 0.34 mg/kg i.p.). Maximal inhibition was reached at approximately 30 min after 0.63 mg/kg F 13640 and fell to half of its value after about 4 to 8 h. After injection (15 min) in the paw pressure test, F 13640 (0.63 mg/kg i.p.) induced an initial hyperalgesia that was followed 4 h later by a paradoxical analgesia that lasted until 8 h. In contrast, in the formalin test, F 13640 inhibited pain behaviors until 4 h after drug administration. F 13640 also produced elements of the 5-HT syndrome that lasted up to 4 h after administration. These results demonstrate that F 13640 induces hyperalgesia and/or analgesia with a time course that parallels the occupancy of 5-HT1A receptors and the presence of the compound in blood and brain.