Neurokinin 3 receptor (NK3R) is the most selective of the tachykinin receptors, with highly preferential binding and activation by its endogenous ligand NKB (TAC3). Importantly, NK3R is mainly expressed in the central nervous system. Besides, a loss-of-function mutation in the gene encoding the neurokinin 3 receptor displays a phenotype of hypogonadotropic hypogonadism. Moreover, the Blockade of NKB-NK3R signaling in the hypothalamus lowers basal LH and estradiol levels and prevents the LH surge, ovulation, and consequent progesterone secretion in the luteal phase of the menstrual cycle.

Hot flushes are a common symptom of menopause that often feels like a sudden flare of heat, paired with sweating and flushed skin. Particularly, Hot flushes are a common symptom of menopause and perimenopause and are often caused by the changing hormone levels that are characteristic of menopause. Specifically, If hot flashes occur at other times in a young female’s menstrual cycle, then it might be a symptom of a problem with her pituitary gland. Because Hot flashes are associated with declining estrogen (estrogen withdrawal) and other hormonal changes.

In this article, we will introduce an NK3R antagonist for menopausal hot flushes, Fezolinetant.

Fezolinetant (ESN-364) (1 mg/kg; i.v. bolus) reversibly inhibits the normal, pulsatile secretion of LH in 3-4 years, 56.6 kg Corriedale ewes. Besides, Fezolinetant (5 mg/kg; p.o.; daily for 5 days) shows lowers plasma LH, but not FSH in castrated monkeys. Moreover, Fezolinetant (10, 25, 50 mg/kg; p.o.; daily for 35 days) blocks the LH surge and decreases ovarian hormone levels throughout the menstrual cycle in monkeys. In addition, Fezolinetant (10, 25, 50 mg/kg; p.o.; daily for 25 days) shows good pharmacokinetic profiles with T_1/2 of 4.3-7.2 h.

All in all, Fezolinetant is a potent NK3R antagonist and decreases the LH pulse frequency and lowers plasma LH without significantly affecting FSH levels. Meanwhile, Fezolinetant also has the potential for researching hot flushes, PCOS, and uterine fibroids.

Reference:

[1] Fraser GL, et al. Endocrinology. 2015 Nov;156(11):4214-25.

[2] Modi M, et al. Neuroendocrinology. 2019;109(3):242-248.