What is the mechanism of action of fezolinetant?

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Fezolinetant is a selective neurokinin 3 receptor (NK3R) antagonist that blocks binding of neurokinin B (NKB) to kisspeptin/neurokinin B/dynorphin (KNDy) neurons to modulate neuronal activity in the thermoregulatory center, helping to restore thermoregulatory balance

  • The thermoregulatory center in the hypothalamus of the brain is innervated by KNDy neurons,1,2 that are inhibited by estrogen and stimulated by the neuropeptide NKB, acting at NK3R, contributing to body temperature regulation.3–7
  • With declining estrogen levels in menopause, NK3R-mediated activation is unopposed5,7 and leads to hypertrophy of KNDy neurons8,9 and altered activity on the thermoregulatory center, triggering heat dissipation effectors.2,3,10,11 Vasodilation in the skin causes heat loss which is experienced as hot flashes, sweating and chills (vasomotor symptoms; VMS).2,12,13
  • Mechanistic studies in ovariectomized rats showed direct actions of fezolinetant on the thermoregulatory center at the median preoptic nucleus (MnPO).14,15

Restoration of thermoregulatory balance by fezolinetant:15

Figure 1. Normal thermoregulation


Figure 2. Disruption of thermoregulatory balance due to reduced estrogen

Figure 3. Mechanism of action of fezolinetant

  1. Krajewski S, Burke M, Anderson M, et al. Forebrain projections of arcuate neurokinin B neurons demonstrated by anterograde tract-tracing and monosodium glutamate lesions in the rat. Neuroscience. 2010;166(2):680-697. Available at: https://doi.org/10.1016/j.neuroscience.2009.12.053.

  2. Padilla SL, Johnson CW, Barker FD, et al. A Neural Circuit Underlying the Generation of Hot Flushes. Cell Rep. 2018;24(2):271-277. Available at: https://doi.org/10.1016/j.celrep.2018.06.037.

  3. Dacks PA, Krajewski SJ, Rance NE. Activation of Neurokinin 3 Receptors in the Median Preoptic Nucleus Decreases Core Temperature in the Rat. Endocrinology. 2011;152(12):4894-4905. Available at: https://doi.org/10.1210/en.2011-1492.

  4. Jayasena CN, Comninos AN, Stefanopoulou E, et al. Neurokinin B Administration Induces Hot Flushes in Women. Sci. Rep. 2015;5(1):8466. Available at: https://doi.org/10.1038/srep08466.

  5. Krajewski-Hall SJ, Blackmore EM, McMinn JR, Rance NE. Estradiol alters body temperature regulation in the female mouse . Temperature (Austin, Tex.). 2017;5(1):56-69. Available at: https://doi.org/10.1080/23328940.2017.1384090.

  6. Ruka KA, Burger LL, Moenter SM. Both Estrogen and Androgen Modify the Response to Activation of Neurokinin-3 and κ-Opioid Receptors in Arcuate Kisspeptin Neurons From Male Mice. Endocrinology. 2016;157(2):752-763. Available at: https://doi.org/10.1210/en.2015-1688.

  7. Mittelman-Smith MA, Williams H, Krajewski-Hall SJ, et al. Role for kisspeptin/neurokinin B/dynorphin (KNDy) neurons in cutaneous vasodilatation and the estrogen modulation of body temperature. Proc. Natl. Acad. Sci. 2012;109(48):19846-19851. Available at: https://doi.org/10.1073/pnas.1211517109.

  8. RANCE NE, McMULLEN NT, SMIALEK JE, et al. Postmenopausal Hypertrophy of Neurons Expressing the Estrogen Receptor Gene in the Human Hypothalamus*. J. Clin. Endocrinol. Metab. 1990;71(1):79-85. Available at: https://doi.org/10.1210/jcem-71-1-79.

  9. Rance N, 3rd YW. Hypertrophy and increased gene expression of neurons containing neurokinin-B and  substance-P messenger ribonucleic acids in the hypothalami of postmenopausal women. Endocrinology. 1991;128(5):2239-2247. Available at: https://doi.org/10.1210/endo-128-5-2239.

  10. Mittelman-Smith MA, Krajewski-Hall SJ, McMullen NT, Rance NE. Neurokinin 3 Receptor-Expressing Neurons in the Median Preoptic Nucleus Modulate Heat-Dissipation Effectors in the Female Rat. Endocrinology. 2015;156(7):2552-2562. Available at: https://doi.org/10.1210/en.2014-1974.

  11. Rance NE, Dacks PA, Mittelman-Smith MA, et al. Modulation of body temperature and LH secretion by hypothalamic KNDy (kisspeptin, neurokinin B and dynorphin) neurons: A novel hypothesis on the mechanism of hot flushes. Front. Neuroendocr. 2013;34(3):211-227. Available at: https://doi.org/10.1016/j.yfrne.2013.07.003.

  12. Krajewski-Hall SJ, Filipa MDS, McMullen NT, et al. Glutamatergic Neurokinin 3 receptor neurons in the median preoptic nucleus modulate heat-defense pathways in female mice. Endocrinology. 2019;(0013-7227) Available at: https://doi.org/10.1210/en.2018-00934.

  13. Dacks P, Rance N. Effects of estradiol on the thermoneutral zone and core temperature in ovariectomized rats. Endocrinology. 2010;151(3):1187-1193. Available at: https://doi.org/10.1210/en.2009-1112.

  14. Tahara A, Tanaka-Amino K, Ohtake A, et al. Fezolinetant attenuates hot flash-like symptoms via inhibition of neuronal activity in the median preoptic nucleus in ovariectomized rats [abstract]. Menopause. 27:1467. Virtual. Available at: https://doi.org/10.1097/GME.0000000000001694.

  15. Depypere H, Lademacher C, Siddiqui E, Fraser GL. Fezolinetant in the treatment of vasomotor symptoms associated with menopause. Expert Opin. Investig. Drugs. 2021;30(7):681-694. Available at: https://doi.org/10.1080/13543784.2021.1893305.

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