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Chemical Compound Review

Flesinoxan     4-fluoro-N-[2-[4-[(8S)-8- (hydroxymethyl)-7...

Synonyms: SureCN220401, CHEMBL1742477, LS-26502, PDSP1_000766, PDSP2_000754, ...
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Psychiatry related information on FLEXINOXAN HYDROCHLORIDE

  • 2. 8-OH-DPAT, flesinoxan and 5-MeO-DMT markedly increased the locomotor activity of naive, unhabituated guinea-pigs in a dose-dependent manner [6].
  • The worsening of symptoms seen with the highest dose of flesinoxan is intriguing and might give a clue to the understanding of the mechanism underlying similar effects seen with antidepressants in panic disorder patients [7].
  • In contrast, pretreatment with flesinoxan (0.1-1 mg/kg, IP) or 8-OH-DPAT (0.1-1 mg/kg, IP) 24 h prior to exposure to stress dose-dependently suppressed the decrease in various exploratory behaviors that was observed immediately after the exposure to acute restraint stress [8].
  • Direct administration of flesinoxan (25.0-50.0 ng) into the DRN induced a significant increment of REM sleep (REMS) during the second and third 2 h of recording [9].
  • Systemic administration of flesinoxan (0.03 and/or 0.06 micromol/kg) significantly increased wakefulness and sleep latencies, and reduced rapid eye movement (REM) sleep and the number of REM periods, during the first and/or second 2-h period after treatment [10].

High impact information on FLEXINOXAN HYDROCHLORIDE

  • This study investigated 5-HT1A receptor occupancy by the 5-HT1A agonist drugs flesinoxan (a highly selective probe for the 5-HT1A receptor) and ziprasidone (a novel atypical antipsychotic drug) [11].
  • The mean cerebral cortex occupancy (+/- 1 SD) for flesinoxan was 8.7% (+/- 13%), and for ziprasidone 4.6% (+/- 17%) [11].
  • Local infusion of the 5-HT(1A) receptor agonist flesinoxan (0.3, 1, 3 microM) for 30 min into the amygdala maximally decreased 5-HT to 50% of basal level [12].
  • For this purpose a series of arylpiperazine congeners of flesinoxan were synthesized and evaluated for their ability to displace [3H]-8-OH-DPAT and [3H]spiperone from their specific binding sites in rat frontal cortex homogenates and rat striatum, respectively [13].
  • Local perfusion of flesinoxan for 30 min through the dialysis probe into the median raphe region at concentrations of 20, 100, and 1,000 nM resulted in a significant decrease in dialysate 5-HT content from both regions [14].

Chemical compound and disease context of FLEXINOXAN HYDROCHLORIDE





  • The effects of flesinoxan in the median raphe (0.3 mg/kg) and dorsal hippocampus (1.0 mg/kg) could be blocked by the 5-HT1A receptor antagonist N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-(2-pyridyl)cyclohexane carboxamide trihydrochloride (WAY 100,635) at a dose of 0.05 mg/kg s.c. The antagonist itself had no effect at this dosage [14].
  • Cardiovascular effects following injection of 8-OH-DPAT and flesinoxan into the dorsal raphe nucleus of conscious rats [23].
  • However, in typically non-5HT1A receptor-containing brain areas Fos-ir is increased due to flesinoxan treatment, as in the paraventricular nucleus of the hypothalamus (PVN), the dorsolateral part of the bed nucleus of the stria terminalis (BNSTdl) and the central amygdala (CeA) [24].
  • In addition, 8-OH-DPAT and flesinoxan caused an increase in phrenic nerve activity [25].
  • When tested against reflexes evoked by stimulation of the sural nerve at strengths between 1.5 and 2.5 times threshold, 8-OH-DPAT (3-300 nmol kg(-1), cumulative) and flesinoxan (22-2200 nmol kg(-1), cumulative) significantly reduced gastrocnemius responses to median values of 36% (IQR 15-75%) and 17% (IQR 12-38%) of pre-drug levels, respectively [26].

Associations of FLEXINOXAN HYDROCHLORIDE with other chemical compounds

  • In a second independent study, 12 healthy volunteers were pretreated sequentially, at one-week intervals, with either the 5-HT1A antagonist pindolol (30 mg, PO), the nonselective 5-HT1/2 antagonist methysergide (4 mg, PO), or placebo, prior to being administered flesinoxan (1 mg, IV) [15].
  • Twenty-four hour after the last pretreatment injection, rats were challenged with flesinoxan (3 mg/kg SC), and the effects on plasma corticosterone and prolactin levels, lower lip retraction and behaviour in the shock-probe burying test were determined [27].
  • OBJECTIVES: We assessed hormonal (ACTH, cortisol, prolactin and growth hormone) and temperature responses to flesinoxan in normal volunteers [28].
  • The selective 5-HT1A receptor antagonist WAY-100635 dose-dependently inhibited the flesinoxan-induced relaxation [29].
  • Anxiolytic compounds such as the benzodiazepine receptor agonists diazepam and alprazolam, the full 5-HT1A receptor agonists 8-OH-DPAT and flesinoxan, and alcohol reduced isolation calling by the guinea pig pup [30].



Analytical, diagnostic and therapeutic context of FLEXINOXAN HYDROCHLORIDE

  • The effects of the selective 5-HT1A receptor agonist flesinoxan on neuroendocrine function, temperature, and behavior were assessed in male healthy volunteers using a double-blind, placebo-controlled crossover design [15].
  • The present results suggest that the growth hormone response and the hypothermic response to the intravenous infusion of flesinoxan may serve as a valid index of 5-HT1A receptor function in humans [15].
  • Initially, the selective antagonist WAY 100635 was used to assess whether or not the changes in aggressive behavior after treatment with 8-OH-DPAT and flesinoxan result from action at the 5-HT1A receptors [36].
  • 4. Microinjections of the non-selective 5-HT1A receptor antagonists, (+/-)-pindolol (2.7 nmol) or methiothepin (5.2 nmol), into the raphe obscurus prevented the increase in blood pressure caused by microinjection of flesinoxan [37].
  • 3. This pattern of excretory response was abolished following acute renal denervation when flesinoxan caused dose-related reductions in urine flow and sodium excretion, similar to that obtained by a mechanical reduction of renal perfusion pressure [3].


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  3. The cardiovascular and renal functional responses to the 5-HT1A receptor agonist flesinoxan in two rat models of hypertension. Chamienia, A.L., Johns, E.J. Br. J. Pharmacol. (1996) [Pubmed]
  4. Agonist occupation of serotonin1A receptors in the rat hippocampus prevents their inactivation by pertussis toxin. Hadrava, V., Blier, P., de Montigny, C. Neuroscience (1994) [Pubmed]
  5. Behavioral and physiological mouse models for anxiety: effects of flesinoxan in 129S6/SvEvTac and C57BL/6J mice. Adriaan Bouwknecht, J., van der Gugten, J., Groenink, L., Olivier, B., Paylor, R.E. Eur. J. Pharmacol. (2004) [Pubmed]
  6. The effect of 5-HT1A receptor agonists on locomotor activity in the guinea-pig. Evenden, J.L. Br. J. Pharmacol. (1994) [Pubmed]
  7. Effects of the 5-HT1A receptor agonist flesinoxan in panic disorder. van Vliet, I.M., Westenberg, H.G., den Boer, J.A. Psychopharmacology (Berl.) (1996) [Pubmed]
  8. Different effects of 5-HT1A receptor agonists and benzodiazepine anxiolytics on the emotional state of naive and stressed mice: a study using the hole-board test. Tsuji, M., Takeda, H., Matsumiya, T. Psychopharmacology (Berl.) (2000) [Pubmed]
  9. Increased REM sleep after intra-dorsal raphe nucleus injection of flesinoxan or 8-OHDPAT: prevention with WAY 100635. Monti, J.M., Jantos, H., Monti, D. European neuropsychopharmacology : the journal of the European College of Neuropsychopharmacology. (2002) [Pubmed]
  10. Differential effects of the 5-HT1A receptor agonist flesinoxan given locally or systemically on REM sleep in the rat. Monti, J.M., Jantos, H. Eur. J. Pharmacol. (2003) [Pubmed]
  11. Occupancy of agonist drugs at the 5-HT1A receptor. Bantick, R.A., Rabiner, E.A., Hirani, E., de Vries, M.H., Hume, S.P., Grasby, P.M. Neuropsychopharmacology (2004) [Pubmed]
  12. Acute and chronic effects of citalopram on postsynaptic 5-hydroxytryptamine(1A) receptor-mediated feedback: a microdialysis study in the amygdala. Bosker, F.J., Cremers, T.I., Jongsma, M.E., Westerink, B.H., Wikström, H.V., den Boer, J.A. J. Neurochem. (2001) [Pubmed]
  13. 5-HT1A-versus D2-receptor selectivity of flesinoxan and analogous N4-substituted N1-arylpiperazines. Kuipers, W., Kruse, C.G., van Wijngaarden, I., Standaar, P.J., Tulp, M.T., Veldman, N., Spek, A.L., IJzerman, A.P. J. Med. Chem. (1997) [Pubmed]
  14. Flesinoxan dose-dependently reduces extracellular 5-hydroxytryptamine (5-HT) in rat median raphe and dorsal hippocampus through activation of 5-HT1A receptors. Bosker, F.J., de Winter, T.Y., Klompmakers, A.A., Westenberg, H.G. J. Neurochem. (1996) [Pubmed]
  15. Serotonin1A receptor activation by flesinoxan in humans. Body temperature and neuroendocrine responses. Seletti, B., Benkelfat, C., Blier, P., Annable, L., Gilbert, F., de Montigny, C. Neuropsychopharmacology (1995) [Pubmed]
  16. Effects of the 5-HT1A receptor ligands flesinoxan and WAY 100635 given systemically or microinjected into the laterodorsal tegmental nucleus on REM sleep in the rat. Monti, J.M., Jantos, H. Behav. Brain Res. (2004) [Pubmed]
  17. Comparison of the cardiovascular effects of the 5-HT1A receptor agonist flesinoxan with that of 8-OH-DPAT in the rat. Dreteler, G.H., Wouters, W., Saxena, P.R. Eur. J. Pharmacol. (1990) [Pubmed]
  18. Antiemetic effects of flesinoxan in cats: comparisons with 8-hydroxy-2-(di-n-propylamino)tetralin. Lucot, J.B. Eur. J. Pharmacol. (1994) [Pubmed]
  19. Tolerance development to the vagal-mediated bradycardia produced by 5-HT1A receptor agonists. McCall, R.B., Escandon, N.A., Harris, L.T., Clement, M.E. J. Pharmacol. Exp. Ther. (1994) [Pubmed]
  20. Renal functional responses to the 5-HT1A receptor agonist flesinoxan: effects of controlled renal perfusion pressure. Chamienia, A.L., Johns, E.J. J. Pharmacol. Exp. Ther. (1994) [Pubmed]
  21. Characterization of 5-hydroxytryptamine1A properties of flesinoxan: in vivo electrophysiology and hypothermia study. Hadrava, V., Blier, P., Dennis, T., Ortemann, C., de Montigny, C. Neuropharmacology (1995) [Pubmed]
  22. Flesinoxan treatment reduces 5-HT1A receptor mRNA in the dentate gyrus independently of high plasma corticosterone levels. Sibug, R.M., Compaan, J.C., Meijer, O.C., Van der Gugten, J., Olivier, B., De Kloet, E.R. Eur. J. Pharmacol. (1998) [Pubmed]
  23. Cardiovascular effects following injection of 8-OH-DPAT and flesinoxan into the dorsal raphe nucleus of conscious rats. Connor, H.E., Higgins, G.A. Br. J. Pharmacol. (1989) [Pubmed]
  24. 5-HT1A receptor agonist flesinoxan enhances Fos immunoreactivity in rat central amygdala, bed nucleus of the stria terminalis and hypothalamus. Compaan, J.C., Groenink, L., van der Gugten, J., Maes, R.A., Olivier, B. Eur. J. Neurosci. (1996) [Pubmed]
  25. Microinjections of 5-HT1A agonists into the dorsal motor vagal nucleus produce a bradycardia in the atenolol-pretreated anaesthetized rat. Sporton, S.C., Shepheard, S.L., Jordan, D., Ramage, A.G. Br. J. Pharmacol. (1991) [Pubmed]
  26. Enhancement and depression of spinal reflexes by 8-hydroxy-2-(di-n-propylamino)tetralin in the decerebrated and spinalized rabbit: involvement of 5-HT1A- and non-5-HT1A-receptors. Clarke, R.W., Ogilvie, J., Houghton, A.K. Br. J. Pharmacol. (1997) [Pubmed]
  27. Flesinoxan pretreatment differentially affects corticosterone, prolactin and behavioural responses to a flesinoxan challenge. Groenink, L., Van der Gugten, J., Compaan, J.C., Maes, R.A., Olivier, B. Psychopharmacology (Berl.) (1997) [Pubmed]
  28. Hormonal and temperature responses to the 5-HT1A receptor agonist flesinoxan in normal volunteers. Pitchot, W., Wauthy, J., Hansenne, M., Pinto, E., Fuchs, S., Reggers, J., Legros, J.J., Ansseau, M. Psychopharmacology (Berl.) (2002) [Pubmed]
  29. In vivo characterization of 5-HT1A receptor-mediated gastric relaxation in conscious dogs. Janssen, P., Prins, N.H., Moreaux, B., Meulemans, A.L., Lefebvre, R.A. Br. J. Pharmacol. (2003) [Pubmed]
  30. Reduction of guinea pig pup isolation calls by anxiolytic and antidepressant drugs. Molewijk, H.E., Hartog, K., van der Poel, A.M., Mos, J., Olivier, B. Psychopharmacology (Berl.) (1996) [Pubmed]
  31. Corticosterone responses in 5-HT1B receptor knockout mice to stress or 5-HT1A receptor activation are normal. Bouwknecht, J.A., van der Gugten, J., Hijzen, T.H., Maes, R.A., Hen, R., Olivier, B. Psychopharmacology (Berl.) (2001) [Pubmed]
  32. Hormonal and temperature responses to flesinoxan in normal volunteers: an antagonist study. Pitchot, W., Wauthy, J., Legros, J.J., Ansseau, M. European neuropsychopharmacology : the journal of the European College of Neuropsychopharmacology. (2004) [Pubmed]
  33. A comparison of the neuro-endocrinological and temperature effects of DU 29894, flesinoxan, sulpiride and haloperidol in normal volunteers. de Koning, P., de Vries, M.H. British journal of clinical pharmacology. (1995) [Pubmed]
  34. Effects of flesinoxan on corticosteroid receptor expression in the rat hippocampus. Sibug, R.M., Compaan, J.C., Meijer, O.C., Van der Gugten, J., Olivier, B., De Kloet, E.R. Eur. J. Pharmacol. (2000) [Pubmed]
  35. Active efflux of the 5-HT(1A) receptor agonist flesinoxan via P-glycoprotein at the blood-brain barrier. van der Sandt, I.C., Smolders, R., Nabulsi, L., Zuideveld, K.P., de Boer, A.G., Breimer, D.D. European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences. (2001) [Pubmed]
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  37. Pressor effects following microinjection of 5-HT1A receptor agonists into the raphe obscurus of the anaesthetized rat. Dreteler, G.H., Wouters, W., Saxena, P.R., Ramage, A.G. Br. J. Pharmacol. (1991) [Pubmed]
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