In recombinant cell lines expressing human 5-HT1A receptors, befiradol exhibits high agonist efficacy for a variety of signal transduction read-outs, including ERK phosphorylation, G-protein activation, receptor internalization and adenylyl cyclase inhibition.[1] In rat hippocampal membranes it preferentially activates GalphaO 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] It has powerful analgesic and antiallodynic effects comparable to those of high doses of opioidpainkillers, but with fewer and less prominent side effects, as well as little or no development of tolerance with repeated use.[3][4][5][6][7]
Befiradol was discovered and developed by Pierre Fabre Médicament, a French pharmaceuticals company. In September 2013, befiradol was out-licensed to Neurolixis, a California-based biotechnology company. Neurolixis announced that it intends to re-purpose befiradol for the treatment of levodopa-induced dyskinesia in Parkinson's disease.[10] In support of this indication, Neurolixis received several research grants[11] from the Michael J. Fox Foundation and preclinical data was published describing the activity of befiradol in animal models of Parkinson's disease.[12][13] In January 2018, the British charity Parkinson's UK announced that it had awarded Neurolixis a grant to advance development of befiradol up to clinical phase in Parkinson's disease patients.[14] In March 2019, Neurolixis announced that the US Food and Drug Administration (FDA) gave a positive response to Neurolixis' Investigational New Drug (IND) application for NLX-112 to be tested in a Phase 2 clinical study in Parkinson's disease patients with troublesome levodopa-induced dyskinesia.[15]
Studies published in 2020 using non-human primate models of Parkinson's disease, (MPTP-treated marmosets and MPTP-treated macaques), found that befiradol potently reduced Levodopa-induced dyskinesia at oral doses as low as 0.1 to 0.4 mg/kg.[16][17]
On 22 November 2020, The Sunday Times reported that the two charities, Parkinson's UK and Michael J. Fox Foundation, were jointly investing $2 million to support a clinical trial on befiradol in Parkinson's disease patients with troublesome Levodopa-induced dyskinesia, a potentially "life changing" drug.[18] On 23 November 2020, Parkinson's UK and Michael J. Fox Foundation, confirmed their funding in an official announcement.[19]Neurolixis announced on 30 November 2021 the start of patient recruitment in the clinical trial.[20] The trial is listed on the U.S. National Library of Medicine clinical trials register.[21]
^ abNewman-Tancredi A, Martel JC, Cosi C, Heusler P, Lestienne F, Varney MA, Cussac D (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.
^Clinical trial number NCT05148884 for "Study to Assess the Safety, Tolerability and Preliminary Efficacy of NLX-112 Versus Placebo in L-dopa-induced Dyskinesia" at ClinicalTrials.gov