In recombinant cell lines expressing human5-HT1A receptors, befiradol exhibits high agonist efficacy for a variety of signal transduction read-outs, includingERK phosphorylation,G-protein activation,receptor internalization andadenylyl cyclase inhibition.[1] In rat hippocampal membranes it preferentially activatesGalphaO proteins.[1] In neurochemical experiments, befiradol activated 5-HT1A autoreceptors in rat dorsal Raphe nucleus as well as 5-HT1A heteroreceptors on pyramidal neurons in the frontal cortex.[2] In rat models, it has powerfulanalgesic andantiallodynic effects comparable to those of high doses ofopioidpainkillers, but with fewer and less prominentside effects, as well as little or no development oftolerance with repeated use.[3][4][5][6][7]
Befiradol was discovered and developed byPierre Fabre Médicament, a French pharmaceuticals company who initially developed it as a treatment for chronic pain. In September 2013, befiradol was out-licensed toNeurolixis, a US-based biotechnology company. Neurolixis announced that it intended to re-purpose befiradol for the treatment oflevodopa-induced dyskinesia inParkinson's disease.[10] In support of this indication, Neurolixis received several research grants[11] from theMichael J. Fox Foundation and preclinical data was published describing the activity of befiradol inanimal models of Parkinson's disease.[12][13] Studies published in 2020 using non-human primate models of Parkinson's disease, (MPTP-treated marmosets andMPTP-treated macaques), found that befiradol potently reducedLevodopa-induced dyskinesia at oral doses as low as 0.1 to 0.4 mg/kg.[14][15] In January 2018, the British charityParkinson's UK announced that it had awarded Neurolixis a grant to advance development of befiradol up to clinical phase in Parkinson's disease patients.[16]
Clinical Ph2A Trial for dyskinesia in Parkinson's disease
As well as studies on befiradol for treatment of movement disorders, other researchers have investigated it as a novel radiotracer for brain imaging studies bypositron emission tomography. Thus befiradol labeled with [18F] (also known as 18F-F13640) has been used to study the distribution of serotonin5-HT1A receptors in rat, cat, macaque and human. Because befiradol is anagonist, it enables the detection of 5-HT1A receptors which are specifically in a functionally active state, whereasantagonist radiotracers label the total receptor population.[23][24]
^abNewman-Tancredi A, Martel JC, Cosi C, Heusler P, Lestienne F, Varney MA, et al. (September 2017). "Distinctive in vitro signal transduction profile of NLX-112, a potent and efficacious serotonin 5-HT1A receptor agonist".The Journal of Pharmacy and Pharmacology.69 (9):1178–1190.doi:10.1111/jphp.12762.PMID28612503.S2CID13676820.
^Lladó-Pelfort L, Assié MB, Newman-Tancredi A, Artigas F, Celada P (May 2012). "In vivo electrophysiological and neurochemical effects of the selective 5-HT1A receptor agonist, F13640, at pre- and postsynaptic 5-HT1A receptors in the rat".Psychopharmacology.221 (2):261–272.doi:10.1007/s00213-011-2569-9.PMID22147258.S2CID18779324.
^Bardin L, Tarayre JP, Malfetes N, Koek W, Colpaert FC (April 2003). "Profound, non-opioid analgesia produced by the high-efficacy 5-HT(1A) agonist F 13640 in the formalin model of tonic nociceptive pain".Pharmacology.67 (4):182–194.doi:10.1159/000068404.PMID12595749.S2CID25882138.
^Bruins Slot LA, Koek W, Tarayre JP, Colpaert FC (April 2003). "Tolerance and inverse tolerance to the hyperalgesic and analgesic actions, respectively, of the novel analgesic, F 13640".European Journal of Pharmacology.466 (3):271–279.doi:10.1016/S0014-2999(03)01566-8.PMID12694810.
^Bardin L, Assié MB, Pélissou M, Royer-Urios I, Newman-Tancredi A, Ribet JP, et al. (March 2005). "Dual, hyperalgesic, and analgesic effects of the high-efficacy 5-hydroxytryptamine 1A (5-HT1A) agonist F 13640 [(3-chloro-4-fluoro-phenyl)-[4-fluoro-4-{[(5-methyl-pyridin-2-ylmethyl)-amino]-methyl}piperidin-1-yl]methanone, fumaric acid salt]: relationship with 5-HT1A receptor occupancy and kinetic parameters".The Journal of Pharmacology and Experimental Therapeutics.312 (3):1034–1042.doi:10.1124/jpet.104.077669.PMID15528450.S2CID42446435.
^Colpaert FC, Deseure K, Stinus L, Adriaensen H (February 2006). "High-efficacy 5-hydroxytryptamine 1A receptor activation counteracts opioid hyperallodynia and affective conditioning".The Journal of Pharmacology and Experimental Therapeutics.316 (2):892–899.doi:10.1124/jpet.105.095109.PMID16254131.S2CID8820667.
^Deseure K, Bréand S, Colpaert FC (July 2007). "Curative-like analgesia in a neuropathic pain model: parametric analysis of the dose and the duration of treatment with a high-efficacy 5-HT(1A) receptor agonist".European Journal of Pharmacology.568 (1–3):134–141.doi:10.1016/j.ejphar.2007.04.022.PMID17512927.
^Bollinger S, Hübner H, Heinemann FW, Meyer K, Gmeiner P (October 2010). "Novel pyridylmethylamines as highly selective 5-HT(1A) superagonists".Journal of Medicinal Chemistry.53 (19):7167–7179.doi:10.1021/jm100835q.PMID20860381.
^Vacher B, Bonnaud B, Funes P, Jubault N, Koek W, Assié MB, et al. (May 1999). "Novel derivatives of 2-pyridinemethylamine as selective, potent, and orally active agonists at 5-HT1A receptors".Journal of Medicinal Chemistry.42 (9):1648–1660.CiteSeerX10.1.1.325.8872.doi:10.1021/jm9806906.PMID10229633.
^Iderberg H, McCreary AC, Varney MA, Kleven MS, Koek W, Bardin L, et al. (September 2015). "NLX-112, a novel 5-HT1A receptor agonist for the treatment of L-DOPA-induced dyskinesia: Behavioral and neurochemical profile in rat".Experimental Neurology.271:335–350.doi:10.1016/j.expneurol.2015.05.021.PMID26037043.S2CID35525495.
^McCreary AC, Varney MA, Newman-Tancredi A (June 2016). "The novel 5-HT1A receptor agonist, NLX-112 reduces l-DOPA-induced abnormal involuntary movements in rat: A chronic administration study with microdialysis measurements".Neuropharmacology.105:651–660.doi:10.1016/j.neuropharm.2016.01.013.PMID26777281.S2CID1979117.
^Depoortere R, Johnston TH, Fox SH, Brotchie JM, Newman-Tancredi A (September 2020). "The selective 5-HT1A receptor agonist, NLX-112, exerts anti-dyskinetic effects in MPTP-treated macaques".Parkinsonism & Related Disorders.78:151–157.doi:10.1016/j.parkreldis.2020.08.009.PMID32846366.S2CID221343904.
^Clinical trial numberNCT05148884 for "Study to Assess the Safety, Tolerability and Preliminary Efficacy of NLX-112 Versus Placebo in L-dopa-induced Dyskinesia" atClinicalTrials.gov
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