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.
To view nearly 50 articles on NLX-112 and NLX-101 see the complete list of publications on PubMed (from US National Library of Medicine)

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

Note: NLX-112 was previously known as F13640 (befiradol) and NLX-101 was previously known as F15599.

 

Selected Publications on NLX-112:

Distinctive in vitro signal transduction profile of NLX-112, a potent and efficacious serotonin 5-HT1A receptor agonist

Newman-Tancredi A, Martel J-C, Cosi C, Heusler P, Lestienne F, Varney MA, Cussac D.
Journal of Pharmacy and Pharmacology, 2017 June 14. DOI: 10.1111/jphp.12762

 

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

 

Antinociceptive, antiallodynic and antihyperalgesic effects of the 5-HT1A receptor selective agonist, NLX-112 in mouse models of pain

Sałat K, Kołaczkowski M, Furgała A, Rojek A, Śniecikowska J, Varney MA, Newman-Tancredi A
Neuropharmacology. 2017 Jul 24;125:181-188. doi: 10.1016/j.neuropharm.2017.07.022.

 

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.