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Neurokinin-3 (NK 3 ) receptors are concentrated in forebrain and basal ganglia structures within the mammalian CNS. This distribution, together with the modulatory influence of NK 3 receptors on monoaminergic neurotransmission, has led to the hypothesis that NK 3 receptor antagonists may have therapeutic efficacy in the treatment of psychiatric disorders. Here we describe the in vitro and in vivo characterization of the highly selective NK 3 receptor antagonist talnetant (SB-223412). Talnetant has high affinity for recombinant human NK 3 receptors (p K i 8.7) and demonstrates selectivity over other neurokinin receptors (p K i NK 2 =6.6 and NK 1 <4). In native tissue-binding studies, talnetant displayed high affinity for the guinea pig NK 3 receptor (p K i 8.5). Functionally, talnetant competitively antagonized neurokinin B (NKB)-induced responses at the human recombinant receptor in both calcium and phosphoinositol second messenger assay systems (pA 2 of 8.1 and 7.7, respectively). In guinea pig brain slices, talnetant antagonized NKB-induced increases in neuronal firing in the medial habenula (pK B =7.9) and senktide-induced increases in neuronal firing in the substantia nigra pars compacta (pK B =7.7) with no diminution of maximal agonist efficacy, suggesting competitive antagonism at native NK 3 receptors. Talnetant (3–30 mg/kg i.p.) significantly attenuated senktide-induced ‘wet dog shake’ behaviors in the guinea pig in a dose-dependent manner. Microdialysis studies demonstrated that acute administration of talnetant (30 mg/kg i.p.) produced significant increases in extracellular dopamine and norepinephrine in the medial prefrontal cortex and attenuated haloperidol-induced increases in nucleus accumbens dopamine levels in the freely moving guinea pigs. Taken together, these data demonstrate that talnetant is a selective, competitive, brain-penetrant NK 3 receptor antagonist with the ability to modulate mesolimbic and mesocortical dopaminergic neurotransmission and hence support its potential therapeutic utility in the treatment of schizophrenia.

Much attention has focused on tachykinin receptors as therapeutic targets for neuropsychiatric disorders, although their expressional distributions in the primate central nervous system (CNS) remain unclear. We cloned the genes encoding the NK‐1 and NK‐3 tachykinin receptors (referred to as rmNK‐1 and rmNK‐3) from the rhesus monkey (Macaca mulatta) brain and examined their pharmacological profiles and regional distributions in the CNS. The deduced rmNK‐1 amino‐acid sequence differed by only two amino acids from the human NK‐1 (hNK‐1). The deduced rmNK‐3 amino‐acid sequence was two amino acids shorter than human NK‐3 (hNK‐3), with a seven‐amino‐acid difference in sequence. Ligand binding studies revealed that the affinity of rmNK‐1 to substance P (SP) was comparable to that of hNK‐1 in cell lines that expressed individual receptors stably. Nonpeptide antagonists had similar effects on the binding of rmNK‐1 and hNK‐1. Affinity of rmNK‐3 for NKB was stronger than for SP and the IC50 value was comparable with that of hNK‐3. Ca2+ imaging showed that activations of both rmNK‐1 and rmNK‐3 by specific ligands, SP and senktide, induced increased intracellular Ca2+ in cell lines that stably expressed individual primate tachykinin receptors. The amounts of rmNK‐1 and rmNK‐3 mRNAs were quantitatively determined in the monkey CNS. The expression of rmNK‐1 was observed in all of the cortical and subcortical regions, including the hippocampus and the amygdala. The putamen contained the most NK‐1 mRNA in the brain, with less rmNK‐3 mRNA found in the cortex compared to rmNK‐1 mRNA. In the monkey hippocampus and amygdala, rmNK‐1 mRNA was present at markedly higher concentrations than rmNK‐3 mRNA. The present results provide an insight into the distinct physiological nature and significance of the NK‐1 and NK‐3 tachykinin systems in the primate CNS. These findings are indispensable for establishing model systems in the search for a subtype‐specific tachykinin receptor agonist and antagonist for the treatment of neuropsychiatric disorders. British Journal of Pharmacology (2006) 147, 316–323. doi:10.1038/sj.bjp.0706561

It has been proposed that antidepressant effects of neurokinin NK1 receptor blockade may result from an increase in serotonin (5-HT) transmission. However, the mechanism by which neurokinins influence 5-HT neurons is not known. In this study, local NK1 and NK3 receptor-mediated responses in 5-HT neurons of the dorsal raphe nucleus (DRN) were studied using intracellular recording in rat brain slices. Bath application of the NK1 receptor agonist substance P (SP) or the NK3 receptor agonists senktide and NKB induced a robust increase in “spontaneous” excitatory postsynaptic currents (EPSCs) in 5-HT neurons. The EPSCs were blocked by the AMPA/kainate glutamate receptor antagonist CNQX and the fast Na+ channel blocker tetrodotoxin (TTX), indicating that the increase in EPSCs resulted from an increase in impulse flow in local glutamatergic neuronal afferents. The neurokinins agonists had no direct excitatory effects on 5-HT neurons and no NK1 or NK3 receptor immunolabeling was found in 5-HT–labeled neurones. However, neurokinins, by increasing excitatory postsynaptic potentials (EPSPs), did increase the spiking of 5-HT neurons. The SP- and NKB-induced EPSCs were preferentially blocked by NK1 and NK3 antagonists, and there was minimal cross-desensitization between agonists at the two receptors. We conclude that neurokinins, via distinct NK1 and NK3 receptors, could promote 5-HT transmission, at least in part, by exciting a local population of glutamatergic inputs to 5-HT neurons in the DRN. However, these local excitatory effects, viewed within the context of the global effects of neurokinins on 5-HT neurons, reveal important differences between the functional role of NK1 and NK3 receptors.

Local pressure‐induced vasodilation (PIV) is a neural vasodilator response to non‐nociceptive externally applied pressure in the skin, previously described in humans. We first determined whether PIV exists in rats and depends on capsaicin‐sensitive fibres as it does in humans. We then examined the mediators involved in the efferent pathway of PIV. Cutaneous blood flow was measured by laser Doppler flowmetry during 11.1 Pa s−1 increases in local applied pressure in anaesthetized rats. The involvement of capsaicin‐sensitive fibres in PIV was tested in rats treated neonatally with capsaicin. To antagonize CGRP, neurokinin‐1, −2, or −3 receptors, different groups of rats were treated with CGRP8–37, SR140333, SR48968 or SR142801, respectively. Prostaglandins involvement was tested with indomethacin treatment. To inhibit nitric oxide synthase (NOS) activity or specific neuronal NOS, rats were treated with NG‐nitro‐L‐arginine or 7‐nitroindazole, respectively. PIV was found in rats, as in humans. PIV was abolished by neonatal treatment with capsaicin and by administration of CGRP8–37 but remained unchanged with SR140333, SR48968 and SR142801 treatments. Prostaglandin inhibition resulted in a significant decrease in PIV. Inhibition of NOS abolished PIV, whereas inhibition of neuronal NOS caused a diminution of PIV. These data suggest that PIV depends on capsaicin‐sensitive fibres in rats, as in humans. It appears that CGRP plays a major role in the PIV, whereas neurokinins have no role. Furthermore, PIV involves a contribution from prostaglandins and depends on endothelial NO, whereas neuronal NO has a smaller role. British Journal of Pharmacology (2000) 131, 1161–1171; doi:10.1038/sj.bjp.0703685

1 Effects of intrathecally (i.t.) injected tachykinin NK‐1 and ‐3 receptor agonists and antagonists were measured on mean arterial blood pressure (MAP) and heart rate (HR) in awake unrestrained spontaneously hypertensive rats (SHR,15‐week‐old) and age‐matched Wistar Kyoto rats (WKY). Quantitative in vitro autoradiography was also performed on the lower thoracic spinal cord of both strains and Wistar rats using specific radioligands for NK‐1 receptor ([125I]HPP[Arg3,Sar9,Met(O2)11]SP (3–11)) and NK‐3 receptor ([125I]HPP‐Asp‐Asp‐Phe‐N‐MePhe‐Gly‐Leu‐Met‐NH2). 2 The NK‐1 agonist [Sar9,Met(O2)11]SP (650 and 6500 pmol) decreased MAP and increased HR in WKY. The fall in MAP was blunted in SHR and substituted by increases in MAP (65–6500 pmol) and more sustained tachycardia. The NK‐3 agonist senktide (6.5–65 pmol) evoked marked increases in MAP and HR (SHR>>>WKY), yet this response was rapidly desensitized. Cardiovascular effects of [Sar9,Met(O2)11]SP (650 pmol) and senktide (6.5 pmol) were selectively blocked by the prior i.t. injection of LY303870 (NK‐1 antagonist, 65 nmol) and SB235375 (NK‐3 antagonist, 6.5 nmol), respectively. Antagonists had no direct effect on MAP and HR in both strains. 3 Densities of NK‐1 and ‐3 receptor binding sites were significantly increased in all laminae of the spinal cord in SHR when compared to control WKY and Wistar rats. The dissociation constant was however not affected in SHR for both NK‐1 (Kd=2.5 nM) and NK‐3 (Kd=5 nM) receptors. 4 Data highlight an upregulation of NK‐1 and ‐3 receptor binding sites in the thoracic spinal cord of SHR that may contribute to the hypersensitivity of the pressor response to agonists and to the greater sympathetic activity seen in this model of arterial hypertension. British Journal of Pharmacology (2006) 148, 25–38. doi:10.1038/sj.bjp.0706694

Hot flushes affect 70% of menopausal women and often severely impact physical, psychosocial, sexual, and overall wellbeing. Hormone replacement therapy is effective but is not without risk. Neurokinin B signalling is increased in menopausal women, and has been implicated as an important mediator of hot flushes. This phase 2, randomised, double-blind, placebo-controlled, single-centre, crossover trial assessed the effectiveness of an oral neurokinin 3 receptor antagonist (MLE4901) on menopausal hot flushes. Eligible participants were healthy women aged 40–62 years, having seven or more hot flushes in every 24 h of which some were reported as being severe or bothersome, who had not had a menstrual period for at least 12 months, and who had not been taking any medication shown to improve menopausal flushes in the preceding 8 weeks. Participants received 4 weeks of MLE4901 (40 mg, orally, twice daily) and placebo (orally, twice daily) in random order separated by a 2 week washout period. Randomisation was completed by a central computer, and participants were allocated to treatment number in numerical order. The primary outcome was the total number of hot flushes during the final week of both treatment periods. Analyses were by intention to treat and per protocol using generalised linear mixed models and standard crossover analysis. All analyses were prespecified in the study protocol. The trial is registered at ClinicalTrials.gov, number NCT02668185. 68 women were screened between Feb 3 and Oct 10, 2016, of which 37 were randomly assigned and included in an intention-to-treat analysis. 28 participants completed the trial and were included in a per-protocol analysis. MLE4901 significantly reduced the total weekly number of hot flushes by 45 percentage points (95% CI 22–67) compared with the placebo (intention-to-treat adjusted means: placebo 49·01 [95% CI 40·81–58·56] vs MLE4901 19·35 [15·99–23·42]; adjusted estimate of difference 29·66 [17·39–42·87], p<0·0001). Treatment was well tolerated. Three participants developed a transaminase rise (alanine aminotransferase 4·5–5·9 times the upper limit of normal) with a normal bilirubin 28 days after starting MLE4901, which normalised within 90 days. Treatment with a neurokinin 3 receptor antagonist (MLE4901) could be practice changing as it safely and effectively relieves hot flush symptoms without the need for oestrogen exposure. Larger scale studies of longer duration are now indicated. UK Medical Research Council and National Institute for Health Research.

1. The aim of this study was to determine whether neurokinin B (NKB) or specific agonists of tachykinin NK(3) receptors, [MePhe(7)]NKB and senktide, were able to induce airway hyperresponsiveness in guinea-pigs. The effects of these compounds were compared to those of substance P (SP), neurokinin A (NKA) and the preferential tachykinin NK(1) ([Sar(9), Met(0(2))(11)]SP) or NK(2) ([betaAla(8)]NKA (4-10)) receptor agonists. 2. In guinea-pigs pretreated with phosphoramidon (10(-4) M aerosol for 10 min) and salbutamol (8.7x10(-3) M for 10 min), all tachykinins administrated by aerosol (3x10(-7) to 10(-4) M) induced airway hyperresponsiveness 24 h later, displayed by an exaggerated response to the bronchoconstrictor effect of acetylcholine (i.v.). The rank order of potency was: [betaAla(8)]NKA (4-10)>NKA=NKB=senktide=[MePhe(7)]NKB=[Sar(9),Met(0(2))(11)]SP>SP. 3. Airway hyperresponsiveness induced by [MePhe(7)]NKB was prevented by the tachykinin NK(3) (SR 142801) and NK(2) (SR 48968) receptor antagonists. 4. Bronchoconstriction induced by tachykinins administered by aerosol was also determined. SP, NKA, NKB and the tachykinin NK(1) and NK(2) receptor agonist induced bronchoconstriction. The rank order of potency was: NKA=[betaAla(8)]NKA (4-10)>NKB=SP=[Sar(9), Met(0(2))(11)]SP. Under similar conditions, and for concentrations which induce airway hyperresponsiveness, senktide and [MePhe(7)]NKB failed to induce bronchoconstriction. 5. It is concluded that tachykinin NK(3)-receptor stimulation can induce airway hyperresponsiveness and that this effect is not related to the ability of tachykinins to induce bronchoconstriction.

In this trial involving women taking endocrine therapy for HR-positive breast cancer, elinzanetant (a neurokinin-targeted therapy) significantly reduced the frequency of moderate-to-severe vasomotor symptoms.

The thermoregulatory center in the hypothalamus is stimulated by neurokinin 3 receptor (NK3R) activation and inhibited by estrogen-negative feedback. This balance is disrupted in menopause, producing vasomotor symptoms (VMSs). To evaluate safety and efficacy of the NK3R antagonist fezolinetant in menopausal VMSs. Twelve-week, double-blind, randomized, placebo-controlled study. Eight Belgian centers from September 2015 to October 2016. Generally healthy menopausal women aged 40 to 65 years with moderate/severe VMSs. Subjects were randomized (1:1) to 90 mg of fezolinetant twice daily or placebo for 12 weeks. Subjects captured VMS severity and frequency using an electronic diary. The primary outcome was change from baseline to week 12 in total VMS score with fezolinetant vs placebo. Secondary outcomes included timing of changes in frequency and severity of moderate/severe VMSs and quality-of-life assessments at weeks 4, 8, and 12. Pharmacodynamic and pharmacokinetic effects were assessed, as were safety and tolerability. Of 122 subjects screened, 87 were randomized and 80 (92%) completed the study. At week 12, fezolinetant significantly reduced total VMS score vs placebo (-26.5 vs -12.2, P < 0.001) and decreased mean frequency of moderate/severe VMSs by five episodes per day vs placebo. Severity and frequency of moderate/severe VMSs were reduced from the first day of treatment. Improvements were achieved in all quality-of-life measures. Fezolinetant was well tolerated. The most common fezolinetant-related adverse event was gastrointestinal disorder (n = 6). Fezolinetant rapidly and significantly reduced moderate/severe VMSs, supporting its potential as an effective nonhormonal treatment option for menopausal women.

Abstract Context Polycystic ovary syndrome (PCOS), a highly prevalent endocrine disorder characterized by hyperandrogenism, is the leading cause of anovulatory infertility. Objective This proof-of-concept study evaluated clinical efficacy and safety of the neurokinin 3 (NK3) receptor antagonist fezolinetant in PCOS. Methods This was a phase 2a, randomized, double-blind, placebo-controlled, multicenter study (EudraCT 2014-004409-34). The study was conducted at 5 European clinical centers. Women with PCOS participated in the study. Interventions included fezolinetant 60 or 180 mg/day or placebo for 12 weeks. The primary efficacy end point was change in total testosterone. Gonadotropins, ovarian hormones, safety and tolerability were also assessed. Results Seventy-three women were randomly assigned, and 64 participants completed the study. Adjusted mean (SE) changes in total testosterone from baseline to week 12 for fezolinetant 180 and 60 mg/day were −0.80 (0.13) and −0.39 (0.12) nmol/L vs −0.05 (0.10) nmol/L with placebo (P < .001 and P < .05, respectively). Adjusted mean (SE) changes from baseline in luteinizing hormone (LH) for fezolinetant 180 and 60 mg/d were −10.17 (1.28) and −8.21 (1.18) vs −3.16 (1.04) IU/L with placebo (P < .001 and P = .002); corresponding changes in follicle-stimulating hormone (FSH) were −1.46 (0.32) and −0.92 (0.30) vs −0.57 (0.26) IU/L (P = .03 and P = .38), underpinning a dose-dependent decrease in the LH-to-FSH ratio vs placebo (P < .001). Circulating levels of progesterone and estradiol did not change significantly vs placebo (P > .10). Fezolinetant was well tolerated. Conclusion Fezolinetant had a sustained effect to suppress hyperandrogenism and reduce the LH-to-FSH ratio in women with PCOS.