Talnetant

Description: IC50 Value: 1.4 nM (hNK-3-CHO binding Ki) [1] Talnetant (SB 223412) is a potent and selective NK3 receptor antagonist. Selectivity studies versus the other neurokinin receptors (hNK-2-CHO and hNK-1-CHO) revealed that Talnetant is about 100-fold selective for the hNK-3 versus hNK-2 receptor, with no affinity for the hNK-1 at concentrations up to 100 microM. in vitro: In vitro studies demonstrated that 53 is a potent functional antagonist of the hNK-3 receptor (reversal of senktide-induced contractions in rabbit isolated iris sphincter muscles and reversal of NKB-induced Ca2+ mobilization in CHO cells stably expressing the hNK-3 receptor), while in vivo this compound showed oral and intravenous activity in NK-3 receptor-driven models (senktide-induced behavioral responses in mice and senktide-induced miosis in rabbits) [1]. Talnetant has high affinity for recombinant human NK3 receptors (pKi 8.7) and demonstrates selectivity over other neurokinin receptors (pKi NK2 = 6.6 and NK1<4). In native tissue-binding studies, talnetant displayed high affinity for the guinea pig NK3 receptor (pKi 8.5) [3]. in vivo: Rectal barostat tests were performed on 102 healthy volunteers, randomized to receive either oral talnetant 25 or 100 mg or placebo over 14-17 days [2]. 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 [3]. Toxicity: Talnetant had no effect on rectal compliance, sensory thresholds or intensity ratings compared with placebo [2]. Clinical trial: Study Of Talnetant Versus Placebo And Risperidone In Schizophrenia. Phase 2

Augmentation of antipsychotic-induced neurochemical changes by the NK3 receptor antagonist talnetant (SB-223412).[Pubmed:18822303]

Neuropharmacology. 2009 Feb;56(2):342-9.

Neurokinin-3 (NK(3)) receptor distribution and its modulatory influence on dopaminergic and noradrenergic neurotransmission have lead to the hypothesis that NK(3) receptor antagonists may be a valid target to ameliorate the symptomatology of schizophrenia. This hypothesis has gained some clinical support as the selective NK(3) receptor antagonist osanetant has shown efficacy in schizophrenic patients. Talnetant (SB-223412) is a potent and selective NK(3) receptor antagonist able to modulate monoaminergic neurotransmission in both cortical and subcortical brain structures. Here we have used in vivo microdialysis to investigate the adjunctive effects of Talnetant (10 and 30 mg/kg; i.p.) on typical (i.e. haloperidol, 0.3 and 1 mg/kg; i.p.) and atypical (i.e. risperidone, 0.3 and 1 mg/kg; i.p.) antipsychotic drug-induced changes in monoaminergic neurotransmission in forebrain structures of the guinea pig. As seen previously Talnetant, produced a dose dependent increase in extracellular levels of both dopamine (DA) and norepinephrine (NE) in both prefrontal cortex (PFC) and hippocampus in a similar manner to the atypical risperidone. Combination studies revealed an additive effect of Talnetant on risperidone-induced changes in both NE and DA levels in the PFC but not the hippocampus. Furthermore, addition of Talnetant converted the neurochemical profile of the typical antipsychotic, haloperidol, to a profile more akin to that induced by an atypical antipsychotic. These data suggest that addition of Talnetant to antipsychotic drugs may facilitate monoaminergic neurotransmission and hence potentially improve their clinical efficacy.

Psychomotor and cognitive effects of a single oral dose of talnetant (SB223412) in healthy volunteers compared with placebo or haloperidol.[Pubmed:18755817]

J Psychopharmacol. 2010 Jan;24(1):73-82.

Central Nervous System (CNS) effects of Talnetant, an NK-3 antagonist in development for schizophrenia, were compared to those of haloperidol and placebo. The study was randomised, double-blind, three-way crossover of Talnetant 200 mg, haloperidol 3 mg or placebo. Twelve healthy males participated and EEG, saccadic and smooth pursuit eye movements, adaptive tracking, body sway, finger tapping, hormones, visual analogue scales (VAS) for alertness, mood and calmness and psychedelic effects, left/right distraction task, Tower of London and Visual and Verbal Learning Task were assessed. Haloperidol showed (difference to placebo; 95% CI; p-value) decreases in EEG alpha power (-0.87microV; -1.51/-0.22; p = 0.0110), saccadic inaccuracy (2.0%; 0.5/3.6; p = 0.0133), smooth pursuit eye movements (-7.5%; -12.0/-3.0; p = 0.0026), adaptive tracking (-3.5%; -5.4/-1.7; p = 0.0009), alertness (-6.8 mm; -11.1/-2.4; p = 0.0039), negative mood (-4.6 mm; -8.6/-0.6; p = 0.0266), the ability to control thoughts (1.2 mm; 0.2/2.3; p = 0.0214), and an increase of serum prolactin (ratio 4.1; 3.0/5.6; p < 0.0001). Talnetant showed decreased alpha power (-0.69 muV; -1.34/-0.04; p = 0.0390), improved adaptive tracking (1.9%; 0.1/3.7; p = 0.0370) and reduced calmness on VAS Bond and Lader (-4.5 mm; -8.0/-1.0; p = 0.0151). Haloperidol effects were predominantly CNS-depressant, while those of Talnetant were slightly stimulatory. The results suggest that Talnetant penetrates the brain, but it remains to be established whether this dose is sufficient and whether the observed effect profile is class-specific for NK3-antagonists.

In vitro and in vivo characterization of the non-peptide NK3 receptor antagonist SB-223412 (talnetant): potential therapeutic utility in the treatment of schizophrenia.[Pubmed:17728699]

Neuropsychopharmacology. 2008 Jun;33(7):1642-52.

Neurokinin-3 (NK3) receptors are concentrated in forebrain and basal ganglia structures within the mammalian CNS. This distribution, together with the modulatory influence of NK3 receptors on monoaminergic neurotransmission, has led to the hypothesis that NK3 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 NK3 receptor antagonist Talnetant (SB-223412). Talnetant has high affinity for recombinant human NK3 receptors (pKi 8.7) and demonstrates selectivity over other neurokinin receptors (pKi NK2 = 6.6 and NK1<4). In native tissue-binding studies, Talnetant displayed high affinity for the guinea pig NK3 receptor (pKi 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 (pA2 of 8.1 and 7.7, respectively). In guinea pig brain slices, Talnetant antagonized NKB-induced increases in neuronal firing in the medial habenula (pKB = 7.9) and senktide-induced increases in neuronal firing in the substantia nigra pars compacta (pKB = 7.7) with no diminution of maximal agonist efficacy, suggesting competitive antagonism at native NK3 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 NK3 receptor antagonist with the ability to modulate mesolimbic and mesocortical dopaminergic neurotransmission and hence support its potential therapeutic utility in the treatment of schizophrenia.

Me-talnetant and osanetant interact within overlapping but not identical binding pockets in the human tachykinin neurokinin 3 receptor transmembrane domains.[Pubmed:18308898]

Mol Pharmacol. 2008 Jun;73(6):1736-50.

Recent clinical trials have indicated that neurokinin 3 receptor antagonists (S)-(+)-N-{{3-[1-benzoyl-3-(3,4-dichlorophenyl)-piperidin-3-yl]prop-1-yl}-4-pheny lpiperidin-4-yl}-N-methylacetamine (SR142801; osanetant) and (S)-(-)-N-(alpha-ethylbenzyl)-3-hydroxy-2-phenylquinoline-4-carboxamide (SB223412; Talnetant) may treat symptoms of schizophrenia. Using site-directed mutagenesis, rhodopsin-based modeling, [(3)H](S)-(-)-N-(alpha-ethylbenzyl)-3-methoxy-2-phenylquinoline-4-carboxamide (Me-Talnetant) and [(3)H]osanetant binding, and functional Schild analyses, we have demonstrated the important molecular determinants of neurokinin B (NKB), Me-Talnetant, and osanetant binding pockets. The residues Asn138(2.57), Asn142(2.61), Leu232(45.49), Tyr315(6.51), Phe342(7.39), and Met346(7.43) were found to be crucial for the NKB binding site. We observed that the M134(2.53)A, V169(3.36)M, F342(7.39)M, and S341(7.38)I/F342(7.39)M mutations resulted in the complete loss of [(3)H]MeTalnetant and [(3)H]osanetant binding affinities and also abolished their functional potencies in an NKB-evoked accumulation of [(3)H]inositol phosphates assay, whereas the mutations V95(1.42)A, N142(2.61)A, Y315(6.51)F, and M346(7.43)A behaved differently between the interacting modes of two antagonists. V95(1.42)A and M346(7.43)A significantly decreased the affinity and potency of Me-Talnetant. Y315(6.51)F, although not affecting Me-Talnetant, led to a significant decrease in affinity and potency of osanetant. The mutation N142(2.61)A, which abolished the potency and affinity of osanetant, led to a significant increase in the affinity and potency of Me-Talnetant. The proposed docking mode was further validated using (S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-((S)-4-m ethanesulfonyl-3-methyl-piperazin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide (RO49085940), from another chemical class. It is noteworthy that the mutation F342(7.39)A caused an 80-fold gain of RO4908594 binding affinity, but the same mutation resulted in the complete loss of the affinity of Me-Talnetant and partial loss of the affinity of osanetant. These observations show that the binding pocket of Me-Talnetant and osanetant are overlapping, but not identical. Taken together, our data are consistent with the proposed docking modes where Me-Talnetant reaches deeply into the pocket formed by transmembrane (TM)1, -2, and -7, whereas osanetant fills the pocket TM3, -5, and -6 with its phenyl-piperidine moiety.

Molecular and pharmacological characterization of the murine tachykinin NK(3) receptor.[Pubmed:11226387]

Eur J Pharmacol. 2001 Feb 16;413(2-3):143-50.

Starting with a partial sequence from Genbank, polymerase chain reaction (PCR) was utilized to isolate the full-length cDNA for NK(3) receptor from mouse brain. The murine NK(3) receptor has a predicted sequence of 452 amino acids, sharing 96% and 86% identity to the rat and human NK(3) receptors, respectively. Binding affinities and functional potencies of tachykinin receptor agonists were similar in HEK (human embryonic kidney) 293 cells expressing murine NK(3) receptor and human NK(3) receptor, although substance P and neurokinin A were more potent stimulators of Ca(2+) mobilization in murine NK(3) receptor cells. NK(3) receptor-selective antagonists from two structural classes, had 10- to 100-fold lower binding affinities for murine NK(3) receptor compared to human NK(3) receptor, and about 5- to 10-fold reduced potency in the murine NK(3) receptor functional assay. The results demonstrate species differences in the potencies of tachykinin receptor antagonists in murine and human NK(3) receptors, and the lower potencies in the former should be taken into consideration when using murine disease models.

Nonpeptide tachykinin receptor antagonists: I. Pharmacological and pharmacokinetic characterization of SB 223412, a novel, potent and selective neurokinin-3 receptor antagonist.[Pubmed:9190866]

J Pharmacol Exp Ther. 1997 Jun;281(3):1303-11.

The in vitro and in vivo pharmacological profile of SB 223412 [(S)-(-)-N-(alpha-ethylbenzyl)-3-hydroxy-2-phenylquinoline-4-carbo xamide], a novel human NK-3 (hNK-3) receptor antagonist, is described. SB 223412 demonstrated enantioselective affinity for inhibition of [125I][MePhe7]neurokinin B (NKB) binding to membranes of CHO cells expressing the hNK-3 receptor (CHO hNK-3). SB 223412, the (S)-isomer, (Ki = 1.0 nM), has similar affinity as the natural ligand, NKB (Ki = 0.8 nM) and another nonpeptide NK-3 receptor antagonist, SR 142801 (Ki = 1.2 nM). SB 223412 was selective for hNK-3 receptors compared with hNK-1 (>10,000-fold selective) and hNK-2 receptors (>140-fold selective), and selectivity was further demonstrated by its lack of effect, in concentrations up to 1 or 10 microM, in >60 receptor, enzyme and ion channel assays. SB 223412 enantioselectively inhibited the NKB-induced Ca++ mobilization in HEK 293 cells stably expressing the hNK-3 receptor. SB 223412 (10-1,000 nM) produced concentration-dependent rightward shifts in NKB-induced Ca++ mobilization concentration-response curves with a Kb value of 3 nM. In addition, SB 223412 antagonized senktide-induced contraction in the isolated rabbit iris sphincter muscle (Kb = 1.6 nM). In mice, oral administration of SB 223412 produced dose-dependent inhibition of behavioral responses induced by the NK-3 receptor-selective agonist, senktide (ED50 = 12.2 mg/kg). Pharmacokinetic evaluation of SB 223412 in rat and dog indicated low plasma clearance, oral bioavailability and high and sustained plasma concentrations after 4 to 8 mg/kg oral dosages. The preclinical profile of SB 223412 (high affinity, selectivity, reversibility and oral activity) suggests that it will be a useful tool compound to define the physiological and pathophysiological roles of NK-3 receptors.

Talnetant (SB 223412) is a potent and selective NK3 receptor antagonist (ki=1.4 nM, hNK-3-CHO); 100-fold selective for the hNK-3 versus hNK-2 receptor, with no affinity for the hNK-1 at concentrations up to 100 uM.

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