Neurokinin-3 Receptor Antagonist Research Articles

What is new on peri- and postmenopause?

Menopause is an increasingly discussed topic in recent years. More women are demanding consultancy and help from their doctors via different channels, be it online or in menopause centers.The term genitourinary syndrome of menopause (GSM) comprises vaginal and urological symptoms such as mucosal dryness, itching and burning, dysuria or bleeding and pain during sexual intercourse. GSM can strongly affect quality of life, is common if estrogen deficiency has lasted for 3 months and can be treated locally with very low doses of the weak estrogen estriol."Not feeling like myself anymore" - symptomatic perimenopause may present with sleep disturbances, mastalgia, mood swings, palpitations, panic attacks, but also entail joint pain, vertigo, headache, and brain fog - even years before menopause and in the presence of still adequate estrogen levels. In an online study, 20% of women in the menopausal transition reported symptoms which they could not explain, and which may cause fears of serious illness. This can lead to extensive medical work-ups if the possibility of perimenopause as the cause is disregarded.(Peri-)menopausal complaints last much longer than previously thought: The Study of women's health across the nation (SWAN) reported longer duration of vasomotor symptoms (median: 11,8 years) in women who were already affected in early perimenopause, while those in whom VMS started only after menopause experienced a shorter duration of symptoms (median: 3,4 years).Female hormones protect women from fatty streaks and hypertension, but menopausal hormone therapy (MHT) has positive effects only if started in the first decade after menopause. The interaction with stress, aging and lifestyle factors is complex.For the treatment of VMS, German and international guidelines list both drug and non-drug or non-prescription options, although there is no clear data on their effectiveness.Fezolinetant, a Neurokinin-3 receptor antagonist, is now available in Germany for the treatment of vasomotor symptoms in postmenopausal women with contraindications or aversion against steroid hormones. It modulates the thermoregulation center in the hypothalamus by blocking the KNDy-neurons. Studies on Elinzanetant, another representative of this class of drugs, are still ongoing.

Validation and Application of Thresholds to Define Meaningful Change in Vasomotor Symptoms Frequency: Analysis of Pooled SKYLIGHT1 and 2 Data.

Vasomotor symptoms (VMS), the characteristic symptoms of menopausal transition, are often the primary reason women seek treatment. Current treatment options for VMS include fezolinetant, a nonhormonal, selective neurokinin3 receptor antagonist. This study aimed to define a clinically meaningful threshold for reduction of moderate-to-severe VMS in postmenopausal women treated with fezolinetant and then apply it in a responder analysis of the pooled trial data. This analysis pooled data from two identical phase3, double-blind, placebo-controlled studies that randomized women with moderate-to-severe VMS to once-daily fezolinetant 30mg, 45mg, or placebo (SKYLIGHT1 and 2). The frequency of VMS was collected daily using an electronic diary. Patients completed the Patient Global Impression of Change in VMS (PGI-C VMS) instrument, which assessed changes in hot flushes/night sweats at weeks4 and 12 compared with baseline using a seven-point Likert scale. VMS frequency data were anchored to PGI-C VMS data; the anchor level for meaningful within-patient change in PGI-C VMS was "moderately better." In the pooled population (N = 1022), the mean (standard deviation) estimated thresholds for a meaningful within-patient change in moderate-to-severe VMS frequency were - 5.73 (3.47) at week4 and - 6.20 (5.18) at week12. Applying the thresholds for meaningful within-patient change to responder analyses ("missing as non-responder" imputation method) indicated a favorable clinical benefit: greater proportions of responders were observed in the fezolinetant 30-mg and 45-mg groups compared with placebo at week4 (odds ratio range 2.48-2.91; P < 0.001) and week12 (odds ratio range 1.908-2.68; P < 0.001). PGI-C VMS is sensitive to change and correlates with VMS frequency: a reduction of approximately six VMS episodes per day from baseline to week12 was meaningful at the individual patient level. Fezolinetant provides a meaningful clinical benefit for women with moderate-to-severe VMS associated with menopause and represents an important nonhormonal treatment option. NCT04003155 and NCT04003142.

Effectiveness and safety of fezolinetant in alleviating vasomotor symptoms linked to Menopause.: A systematic review and Meta-Analysis

Background & ObjectiveVasomotor symptoms (VMS) are the most common symptoms during menopause including hot flushes and night sweats. They are highly disruptive to the quality of life. Fezolinetant is an FDA-approved non-hormonal selective neurokinin3 receptor antagonist for the treatment of VMS. In this study, we aim to assess the efficacy and safety of fezolinetant for VMS associated with menopause. MethodsDatabases were searched until September 2023 for relevant studies comparing fezolinetant against placebo. Data was extracted into an online form and analyzed using RevMan (Version 5.4.1). The GRADE approach was conducted to evaluate the quality of evidence regarding efficacy outcomes. We included randomized controlled trials (RCTs) comparing fezolinetant to placebo in postmenopausal women experiencing VMS. Exclusion criteria comprised studies involving participants with contraindications to fezolinetant or those evaluating its efficacy for indications other than VMS associated with menopause. ResultsSix studies were included in this study involving 3301 patients. Compared to placebo, fezolinetant reduced the frequency of VMS episodes from baseline (SMD = -0.64, 95 % CI [-0.77, −0.5]) and (SMD = -0.63, 95 % CI [-0.72, −0.53] at weeks 4 and 12 respectively. Additionally, fezolinetant reduced VMS severity score (SMD = -0.59, 95 %CI [-0.77, −0.42]) and (SMD = -0.4, 95 % CI [-0.54, −0.27]) at weeks 4 at 12 respectively. These reductions were positively reflected on Menopause specific quality of life score (SMD = -0.46, 95 %CI [-57, −0.34]), (SMD = -0.37, 95 %CI [-0.48, −0.25]) at weeks 4 and 12 respectively. Regarding safety analysis, fezolinetant showed increased risk for drug-related TEAEs (RR = 1.47, 95 %CI [1.06,2.04]), serious TEAEs (RR = 1.67, 95 %CI [1.09,2.55]), fatigue (RR = 4.05, 95 %CI [1.27,12.88]), arthralgia (RR = 2.83, 95 %CI [1.02,7.8]) and ALT or AST > 3 times (RR = 2, 95 %CI [1.12,3.57]), with no other statistically significant difference regarding other safety terms. ConclusionFezolinetant has demonstrated efficacy in reducing the frequency and severity of VMS in postmenopausal women, leading to an improvement in their quality of life. These findings suggest that Fezolinetant may serve as a viable alternative to hormonal therapy for managing VMS.

NK3R signalling in the posterodorsal medial amygdala is involved in stress-induced suppression of pulsatile LH secretion in female mice.

Psychosocial stress negatively impacts reproductive function by inhibiting pulsatile luteinizing hormone (LH) secretion. The posterodorsal medial amygdala (MePD) is responsible in part for processing stress and modulating the reproductive axis. Activation of the neurokinin 3 receptor (NK3R) suppresses the gonadotropin-releasing hormone (GnRH) pulse generator, under hypoestrogenic conditions, and NK3R activity in the amygdala has been documented to play a role in stress and anxiety. We investigate whether NK3R activation in the MePD is involved in mediating the inhibitory effect of psychosocial stress on LH pulsatility in ovariectomised female mice. First, we administered senktide, an NK3R agonist, into the MePD and monitored the effect on pulsatile LH secretion. We then delivered SB222200, a selective NK3R antagonist, intra-MePD in the presence of predator odour, 2,4,5-trimethylthiazole (TMT) and examined the effect on LH pulses. Senktide administration into the MePD dose-dependently suppresses pulsatile LH secretion. Moreover, NK3R signalling in the MePD mediates TMT-induced suppression of the GnRH pulse generator, which we verified using a mathematical model. The model verifies our experimental findings: (i) predator odour exposure inhibits LH pulses, (ii) activation of NK3R in the MePD inhibits LH pulses and (iii) NK3R antagonism in the MePD blocks stressor-induced inhibition of LH pulse frequency in the absence of ovarian steroids. These results demonstrate for the first time that NK3R neurons in the MePD mediate psychosocial stress-induced suppression of the GnRH pulse generator.

A novel role of NK3 receptor signaling in bipolar disorder

Objective: Bipolar disorder (BD) affects more than 1% of the global population with limited therapeutic options. The neurokinin B (NKB)-neurokinin B receptor (NK3R) is involved in a variety of emotional activities. This study explored the role of NK3 receptor signaling in bipolar disorder.Materials and methods: In this study, a model of intracerebroventricular (ICV) administration of OUA-induced BD was used to investigate the possible role of NK3R signaling in BD. The involvement of NK3R in the expression of OUA-induced BD was assessed by genetically knocking down the NK3R-encoding TACR3 gene with shRNA approach in the hippocampus and systemic administration of a NK3R antagonist ESN364,. Biochemical techniques were used to examine the NK3R-associated signaling changes and the oxidative stress parameters in the hippocampus of BD rats.Result: The NK3R expression level was elevated in the hippocampus BD rats. Both TACR3 knockdown in the hippocampus and ESN364 treatment reversed the manic-like and depression-like behaviors in BD rats Inhibition of the NK3R signaling reversed oxidative stress-induced damage via upregulating the BDNF signaling pathway in the hippocampus.Conclusion: These results demonstrated that NK3R signaling plays a key role in the pathogenesis of BD and that pharmacological antagonist of NK3R such as ESN364 could represent a novel therapeutic strategy for the management of BD.

A Nonhormonal Selective NK3R Antagonist for Moderate to Severe Vasomotor Symptoms in Menopause.

A Nonhormonal Selective NK3R Antagonist for Moderate to Severe Vasomotor Symptoms in Menopause.

A Nonhormonal Selective NK3R Antagonist for Moderate to Severe Vasomotor Symptoms in Menopause.

A Nonhormonal Selective NK3R Antagonist for Moderate to Severe Vasomotor Symptoms in Menopause.

Treatment of women with vasomotor symptoms with neurokinin-3 receptor antagonist Fezolinetant

Treatment of women with vasomotor symptoms with neurokinin-3 receptor antagonist Fezolinetant

Synthesis and evaluation of piperazinotriazoles. Discovery of a potent and orally bioavailable neurokinin-3 receptor inhibitor

The neurokinin-3 receptor (NK3R) is one of three receptors that recognize neurokinins. The finding that pharmacological blockade of neurokinin B (NKB) signaling with an oral NK3R antagonist can significantly improve hot flash symptoms independent of any hormonal effect fits strongly suggest that NK3R is a viable drug target and that drugs targeting this receptor could be novel pharmacotherapies. Currently no NK3R ligands have been approved for the treatment of human disorders. Herein, we designed and synthesized a series of novel imidazolepiperazine derivatives (16a-16x, 20a-20f, 29a-29m) and performed molecular docking to confirm the design, among which the target compound 16x exhibited promising inhibitory activity against NK3R (IC50 = 430.60 nM) with excellent membrane permeability (Papp, A-B = 37.6 × 10−6 cm/s, ER < 1) and oral bioavailability (F% = 93.6%). Our in vivo studies demonstrated that 16x was orally active, efficacious, and well-tolerated in ovariectomy (OVX) model to suppress blood luteinizing hormone levels, which suggests that 16x is a viable lead compound for further optimization and development.

The overexpression of neurokinin B-neurokinin 3 receptor system exerts direct effects on the ovary under PCOS-like conditions to interfere with mitochondrial function.

The increased hypothalamic neurokinin B (NKB) level may contribute to the hyperactive LH pulse secretion in Polycystic ovary syndrome (PCOS). However, the expression and role of the neurokinin B-neurokinin 3 receptor (NKB-NK3R) system in the local ovarian tissue of PCOS have not been clarified. We constructed in vivo and in vitro models to elucidate the mechanism of the NKB-NK3R pathway in reproductive endocrine disorders of PCOS. The granulosa cell line-KGN cells were set in palmitic acid (PA) and dihydrotestosterone (DHT) to simulate the PCOS-like conditions. And we used the high-fat/high-glucose diet to build a PCOS-like mice model and neurokinin 3 receptor antagonist (NK3Ra) was administered to half of the mice. The expression of the NKB-NK3R system, mitochondrial functions, hormone levels, and inflammatory state was evaluated. The PCOS-like stimulations induced the NKB-NK3R system and MAPK-ERK pathway overexpression in KGN cells, in an approximate dose and time-dependent manner. The NKB-NK3R system overactivated the MAPK-ERK pathway to increase NNT overexpression, disturb NADH/NADPH pools, aggravate the oxidation state, and decrease ATP production. With overexpression of the NKB-NK3R system in the local ovarian tissue, ovulatory dysfunction, progesterone deficiency, and pro-inflammatory states were apparent in PCOS-like mice. Antagonizing the receptor, NK3R, reversed the adverse reproductive endocrine phenotypes via improving mitochondrial dysfunction. In addition to the central regulation, local ovarian overexpression of the NKB-NK3R system participated in the adverse reproductive endocrine phenotypes, supporting the therapeutic implications of NK3Ra for PCOS.

OR06-5 Fezolinetant for Treatment of Moderate-to-severe Vasomotor Symptoms Associated with Menopause: Results from a 52-week Study (Skylight 2)

Abstract Background SKYLIGHT 2 (NCT04003142) investigated safety and efficacy of fezolinetant (a neurokinin-3 receptor antagonist) on frequency and severity of moderate-to-severe vasomotor symptoms (VMS) and sleep disturbance. In this analysis, persistence of fezolinetant efficacy was investigated over 52 weeks. Methods This double-blind Phase 3 study randomized women aged ≥40–65 years with moderate-to-severe VMS associated with menopause (average of ≥7 hot flashes/day) to once-daily placebo or fezolinetant 30mg or 45mg for 12 weeks. Women completing 12 weeks entered an extension period, with those on placebo re-randomized to fezolinetant 30mg or 45mg (placebo/fezolinetant), and those originally on fezolinetant remaining on their dose for an additional 40-weeks. Fezolinetant efficacy was evaluated vs placebo for 12-weeks through change in VMS frequency, VMS severity, and Patient-reported Outcomes Measurement Information System Sleep Disturbance–Short Form 8b (PROMIS) Total Score. Persistence of efficacy for fezolinetant was evaluated descriptively (without statistical comparisons) over the extension period. Results The analysis comprised 484 women (fezolinetant 30mg n=166, fezolinetant 45mg n=167, placebo/fezolinetant 30mg n=76, placebo/fezolinetant 45mg n=75). Improvement in VMS frequency and severity observed through week 12 (statistically significant differences vs placebo) was maintained throughout the 52-week total study period for those receiving fezolinetant. Fezolinetant demonstrated further reductions in VMS frequency and severity from baseline to beyond week 12. For VMS frequency, there was a least squares (LS) mean (SE) baseline-to-week 12 reduction of –6.83 (0.39) VMS/day for fezolinetant 30mg and –7.50 (0.39) for 45mg, and a mean (SD) baseline-to-week 52 reduction of –8.03 (4.53) for fezolinetant 30mg and –8.48 (3.98) for 45mg. For VMS severity, LS mean (SE) baseline-to-week 12 reduction was –0.64 (0.06) for 30mg and –0.77 (0.06) for 45mg, and mean (SD) baseline-to-week 52 reduction was –0.83 (0.82) for fezolinetant 30mg, and –0.95 (0.78) for 45mg. Women re-randomized from placebo to fezolinetant experienced a reduction in frequency and severity of VMS consistent with that in women receiving fezolinetant throughout the study. Fezolinetant also reduced PROMIS-assessed sleep disturbance, with a LS mean (SE) baseline-to-week 12 reduction of –4.1 (0.5) for fezolinetant 30mg and –5.5 (0.5) for 45mg (statistically significant difference vs placebo for fezolinetant 45mg) and a mean (SD) baseline-to-week 52 reduction of – 6.3 (7.3) for fezolinetant 30mg and –5.7 (7.9) for 45mg. The safety profile observed for the 40-week extension period was consistent with that of the 12-week placebo-controlled period. Conclusion Fezolinetant 30mg and 45mg once daily were efficacious for treatment of moderate-to-severe VMS associated with menopause. Efficacy was persistent and reductions in VMS frequency were maintained during the extension period, at levels consistent with weeks 1 through 12. Fezolinetant 45mg improved sleep at week 12 and improvement was maintained through the active treatment extension period. No safety signals of concern were apparent for either fezolinetant dose. Presentation: Saturday, June 11, 2022 12:30 p.m. - 12:45 p.m.

Pharmacological Antagonism of the Kisspeptin-Neurokinin System Improved Adverse Metabolic Traits in a PCOS Mouse Model

Background: Polycystic ovary syndrome (PCOS) is a heterogeneous endocrine condition affecting up to 20% of reproductively aged women worldwide. Owing to an ambiguous etiology and complicated pathophysiology, current PCOS treatments remain purely symptomatic. Aberrations in androgen receptor driven neuroendocrine pathways are reportedly involved in the pathogenesis of PCOS. A clinical trial, focusing on the androgen regulated kisspeptin-neurokinin B-dynorphin system, treated women with PCOS with a neurokinin B receptor (neurokinin 3 receptor, NK3R) antagonist and reported improvements in LH secretion, LH pulses and testosterone levels. Aim: To investigate if pharmacological antagonism of NK3R can ameliorate PCOS traits in a mouse model. Method: Reproductive and metabolic features of PCOS were evaluated in control and dihydrotestosterone (DHT)-induced PCOS mice, treated +/-NK3R antagonist (MLE4901) for 28 days at a dose of 25mg/kg/day. Results: PCOS-like mice were acyclic and exhibited ovulatory dysfunction, which were not rescued by NK3R antagonist treatment. Compared to control mice, the PCOS-like mice displayed a significant increase in total body weight and inguinal, parametrial, mesenteric, retroperitoneal, and brown fat pad weights (all P[Formula: see text]0.01). NK3R antagonism partially reversed the total body weight and fat pad weight gains (all P[Formula: see text]0.01) in all white fat depots of PCOS-like mice. PCOS-like mice also displayed adipocyte hypertrophy and increased leptin levels compared to control mice (both P[Formula: see text]0.01), which were improved with NK3R antagonism treatment (P[Formula: see text]0.01 and P[Formula: see text]0.05, respectively). Moreover, DHT exposure significantly reduced the respiratory exchange ratio (RER) (P[Formula: see text]0.01), whereas NK3R antagonism significantly increased RER compared to control mice (P[Formula: see text]0.01), suggesting a metabolic shift in the PCOS-like mice treated with the NKR3 antagonist. Conclusion: These findings show that pharmacological antagonism of the kisspeptin-neurokinin system may be a beneficial treatment for adverse metabolic features of PCOS. This study also reveals important new insights into neuroendocrine androgen actions in the pathogenesis of PCOS.

A Phase-3, Randomized, Placebo-Controlled, 12-Week, Double-Blind Study to Assess Efficacy and Safety of Fezolinetant, a Neurokinin-3 Receptor Antagonist, in Women with Moderate-to-Severe Vasomotor Symptoms Associated with Menopause

A Phase-3, Randomized, Placebo-Controlled, 12-Week, Double-Blind Study to Assess Efficacy and Safety of Fezolinetant, a Neurokinin-3 Receptor Antagonist, in Women with Moderate-to-Severe Vasomotor Symptoms Associated with Menopause

Functional Rescue of Inactivating Mutations of the Human Neurokinin 3 Receptor Using Pharmacological Chaperones.

G protein-coupled receptors (GPCRs) facilitate the majority of signal transductions across cell membranes in humans, with numerous diseases attributed to inactivating GPCR mutations. Many of these mutations result in misfolding during nascent receptor synthesis in the endoplasmic reticulum (ER), resulting in intracellular retention and degradation. Pharmacological chaperones (PCs) are cell-permeant small molecules that can interact with misfolded receptors in the ER and stabilise/rescue their folding to promote ER exit and trafficking to the cell membrane. The neurokinin 3 receptor (NK3R) plays a pivotal role in the hypothalamic–pituitary–gonadal reproductive axis. We sought to determine whether NK3R missense mutations result in a loss of cell surface receptor expression and, if so, whether a cell-permeant small molecule NK3R antagonist could be repurposed as a PC to restore function to these mutants. Quantitation of cell surface expression levels of seven mutant NK3Rs identified in hypogonadal patients indicated that five had severely impaired cell surface expression. A small molecule NK3R antagonist, M8, increased cell surface expression in four of these five and resulted in post-translational receptor processing in a manner analogous to the wild type. Importantly, there was a significant improvement in receptor activation in response to neurokinin B (NKB) for all four receptors following their rescue with M8. This demonstrates that M8 may have potential for therapeutic development in the treatment of hypogonadal patients harbouring NK3R mutations. The repurposing of existing small molecule GPCR modulators as PCs represents a novel and therapeutically viable option for the treatment of disorders attributed to mutations in GPCRs that cause intracellular retention.

The roles of kisspeptin and neurokinin B in GnRH pulse generation in humans, and their potential clinical application.

The delivery of gonadotropin-releasing hormone (GnRH) in a pulsatile mode to the gonadotropes has long been known to be essential for normal reproductive function. There have been numerous studies aimed at dissecting out the mechanisms underlying GnRH pulse generation. The discovery of kisspeptin as an upstream regulator of GnRH attracted the possibility that pulsatile kisspeptin governed the pulsatile secretion of GnRH. Subsequent studies have shown the importance of the neurokinin B (NKB) system in modulating kisspeptin secretion and this GnRH. A number of studies in laboratory rodents have supported this notion. By contrast, we present data from clinical studies in men and women, in a range of contexts, showing that continuous infusion of kisspeptin 10 at receptor-saturating levels gives rise to an increase in luteinizing hormone (LH) (GnRH) pulse frequency. This has been demonstrated in normal healthy and hypogonadal men, in normal women during the mid-cycle LH surge, in men and women with mutations in the genes encoding NKB or its receptor, neurokinin 3 receptor (NK3R), in women with polycystic ovary syndrome treated with NK3R antagonist, and in women treated with NK3R antagonist during the LH surge. These finds indicate that pulsatile secretion and action of kisspeptin on GnRH neurons is not required for the generation of LH (GnRH) pulses in humans. We also report that there is an absence of desensitization in humans exposed to continuous infusion of kisspeptin-10 at receptor-saturating concentrations over 22h and briefly review GnRH, kisspeptin and NKB analogs and their clinical application.

Fezolinetant in the treatment of vasomotor symptoms associated with menopause

ABSTRACT Introduction: Although international clinical practice guidelines recognize a continued role for menopausal hormone therapy (HT), particularly for symptomatic women <60 years of age or within 10 years of menopause, safety and tolerability concerns have discouraged HT use due to potential links with a perceived increased risk of hormone-dependent cancers, and an established risk of stroke and venous thromboembolism. There is therefore a need for safe, effective non-hormonal therapy for relief of menopausal vasomotor symptoms (VMS). Areas covered: This narrative review summarizes the dataset accrued for fezolinetant, a neurokinin-3 receptor (NK3R) antagonist in clinical development for menopause-associated VMS. Expert opinion: Altered signaling in neuroendocrine circuits at menopause leads to VMS wherein NK3R activity plays a key role to modulate the thermoregulatory center in a manner conducive to triggering the ‘hot flash’ response. Thus, a new generation of NK3R antagonists has entered clinical development to specifically target the mechanistic basis of VMS. Fezolinetant is the most advanced NK3R antagonist in terms of stage of clinical development. Results to date have demonstrated rapid and substantial reduction in VMS frequency and severity and associated improvements in health-related quality of life. NK3R antagonists offer a non-hormonal alternative to HT for the treatment of menopause-related VMS.

Different pituitary action of NK3Ra and NK3Rb in grass carp

In mammals, NK3R is the specific receptor for NKB, which played an important role in reproduction. Recently, two NK3R isoforms, namely NK3Ra and NK3Rb, have been identified in fish. However, little is known about the pituitary actions of the two NK3R isoforms in fish. In this study, both NK3Ra and NK3Rb were isolated from grass carp pituitary. Although their sequence similarity was only 61.6%, the two NK3R isoforms displayed similar ligand selectivity and binding affinity to TAC3 gene products (NKBa, NKBRPa and NKBRPb). In addition, both NK3Ra and NK3Rb displayed similar signaling pathways, including PKA, PKC, MAPK and Ca2+ cascades. Tissue distribution indicated that both NK3Ra and NK3Rb were highly detected in grass carp pituitary. Further study found that NK3Ra was mainly located in pituitary LHβ cells, while NK3Rb was only detected in pituitary SLα cells. Furthermore, NK3Ra and NK3Rb activation could induce LHβ and SLα promoter activity, respectively. These results suggested that the two NK3R isoforms displayed different pituitary actions in fish. Using grass carp pituitary cells as model, we found that PACAP could significantly reduce NK3Ra, but induce NK3Rb mRNA expression coupled with cAMP/PKA and PLC/PKC pathways. Interestingly, PACAP could also significantly inhibit LHβ, but stimulate SLα mRNA expression in grass carp pituitary cells. Furthermore, NK3R antagonist could not only inhibit LHβ mRNA expression, but also block PACAP-induced SLα mRNA expression in grass carp pituitary cells. These results suggested that NK3Ra and NK3Rb could mediate PACAP-reduced LHβ and -induced SLα mRNA expression in grass carp pituitary, respectively.

Effects of neurokinin 3 receptor antagonist fezolinetant on hot flash-like symptoms in ovariectomized rats

The majority of women experience vasomotor symptoms (VMS), such as hot flashes and night sweats, during the menopausal transition. Recent evidence strongly suggests a connection between neurokinin 3 (NK3) receptor signaling and VMS associated with menopause. The NK3 receptor antagonist fezolinetant is currently in phase 3 development for treatment of moderate to severe VMS associated with menopause. We investigated the pharmacological effects of repeated administration of fezolinetant on levels of sex hormones and gonadotropins, neuronal activity in the hypothalamus, and skin temperature as an index of hot flash-like symptoms in ovariectomized rats as a model of menopause. Ovariectomized rats exhibited several typical menopausal symptoms: hyperphagia, increased body weight, significantly decreased plasma estradiol levels, increased luteinizing hormone (LH) and follicle-stimulating hormone (FSH) levels, and significantly increased skin temperature. Increased c-Fos expression (an indirect marker of neuronal activity) in median preoptic nucleus (MnPO) hypothalamic neurons was also observed in ovariectomized rats. Repeated oral administration of fezolinetant (1–10 mg/kg, twice daily) for 1 week dose-dependently reduced plasma LH levels without affecting estradiol or FSH levels, inhibited the activation of MnPO neurons, and attenuated hot flash-like symptoms. In addition, fezolinetant dose-dependently reduced hyperphagia and weight gain in ovariectomized rats. These preclinical findings suggest that fezolinetant attenuates hot flash-like symptoms via inhibition of neuronal activity in the MnPO of ovariectomized rats and provides further support for the ongoing clinical development of fezolinetant for the treatment of VMS associated with menopause.

Neurokinin 3 Receptor Antagonism Ameliorates Key Metabolic Features in a Hyperandrogenic PCOS Mouse Model.

Polycystic ovary syndrome (PCOS) is a prevalent endocrine condition characterized by a range of endocrine, reproductive, and metabolic abnormalities. At present, management of women with PCOS is suboptimal as treatment is only symptomatic. Clinical and experimental advances in our understanding of PCOS etiology support a pivotal role for androgen neuroendocrine actions in PCOS pathogenesis. Hyperandrogenism is a key PCOS trait and androgen actions play a role in regulating the kisspeptin-/neurokinin B-/dynorphin (KNDy) system. This study aimed to investigate if targeted antagonism of neurokinin B signaling through the neurokinin 3 receptor (NK3R) would reverse PCOS traits in a dihydrotestosterone (DHT)-induced mouse model of PCOS. After 3 months, DHT exposure induced key reproductive PCOS traits of cycle irregularity and ovulatory dysfunction, and PCOS-like metabolic traits including increased body weight; white and brown fat pad weights; fasting serum triglyceride and glucose levels, and blood glucose incremental area under the curve. Treatment with a NK3R antagonist (MLE4901) did not impact the observed reproductive defects. In contrast, following NK3R antagonist treatment, PCOS-like females displayed decreased total body weight, adiposity, and adipocyte hypertrophy, but increased respiratory exchange ratio, suggesting NK3R antagonism altered the metabolic status of the PCOS-like females. NK3R antagonism did not improve circulating serum triglyceride or fasted glucose levels. Collectively, these findings demonstrate that NK3R antagonism may be beneficial in the treatment of adverse metabolic features associated with PCOS and support neuroendocrine targeting in the development of novel therapeutic strategies for PCOS.

Commentary on "Pharmacodynamic Activity of the Novel Neurokinin-3 Receptor Antagonist SJX-653 in Healthy Men".

Commentary on "Pharmacodynamic Activity of the Novel Neurokinin-3 Receptor Antagonist SJX-653 in Healthy Men".