Disease relevance of Talnetant

• Studies with talnetant and other selective NK3 receptor antagonists are, therefore, revealing an exciting and novel pathway by which pathological changes in intestinal motility and nociception can be induced, suggesting a role for NK3 receptor antagonism in irritable bowel syndrome [1].
• Senktide-induced miosis was inhibited by SB 222200 (1 and 2 mg kg[-1], i.v., i.e. 2.63 and 5.26 micromol kg[-1]; maximum inhibition 100%; n=3-4), SB 223412 (0.5 and 1 mg kg[-1], i.v., i.e. 1.31 and 2.61 micromol kg[-1]; maximum inhibition 100%; n=3), SB 218795 (0.5 and 1 mg kg[-1] i.v., i.e. 1.26 and 2 [2].
• This study was designed to determine whether NK3 receptor antagonists crossing (talnetant) or not (SB-235375) the blood-brain barrier reduce the nociceptive response to colo-rectal distension (CRD) and whether NK3 antagonism reduces inflammation- or stress-induced hypersensitivity to rectal distension [3].

High impact information on Talnetant

• Overall, the biological data indicate that (S)-N-(1-phenylpropyl)-3-hydroxy-2-phenylquinoline-4-carboxamide (53, SB 223412) may serve as a pharmacological tool in animal models of disease to assess the functional and pathophysiological role of the NK-3 receptor and to establish therapeutic indications for non-peptide NK-3 receptor antagonists [4].
• SB 223412 enantioselectively inhibited the NKB-induced Ca++ mobilization in HEK 293 cells stably expressing the hNK-3 receptor [5].
• Nonpeptide tachykinin receptor antagonists: I. Pharmacological and pharmacokinetic characterization of SB 223412, a novel, potent and selective neurokinin-3 receptor antagonist [5].
• 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) [5].
• In addition, SB 223412 antagonized senktide-induced contraction in the isolated rabbit iris sphincter muscle (Kb = 1.6 nM) [5].

Chemical compound and disease context of Talnetant

• Other clinical candidates (for central nervous system disorders: osanetant, talnetant and saredutant; for irritable bowel syndrome: nepadutant and saredutant) are in advanced clinical phase [6].

Biological context of Talnetant

• 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 [5].
• We have examined the effects of the NK(3) receptor antagonist, talnetant, on peristalsis in guinea-pig isolated ileum induced by optimal and by supra-maximal distension pressures [7].

Anatomical context of Talnetant

• 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) [5].
• 3 Peristaltic waves in the ileum elicited by optimal distension pressures (1-3 cmH(2)O) were unaffected by talnetant at a supra-maximal concentration (250 nm) [7].

Associations of Talnetant with other chemical compounds

• Talnetant (3-30 mg/kg i.p.) significantly attenuated senktide-induced 'wet dog shake' behaviors in the guinea pig in a dose-dependent manner [8].

Gene context of Talnetant

• 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 [5].
• 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 [5].

Analytical, diagnostic and therapeutic context of Talnetant

• Fluoroiodo-2-phenylquinoline-4-carboxamides, analogues of NK-3 antagonist SB 223412, were synthesized and evaluated as NK-3 ligands with the aim of developing radioligands suitable for both Positron Emission Tomography (PET) and Single Photon Emission Computed Tomography (SPECT) studies [9].

References