Journal Article

In Vitro and In Vivo Characterization of the Non-peptide NK3 Receptor Antagonist SB-223412 (Talnetant): Potential Therapeutic Utility in the Treatment of Schizophrenia

Dawson, Lee A, Wood, Martyn D, Hagan, Jim, Jones, Declan NC, Scott, Claire, de la Flor, Raúl, Cluderay, Jane E, Watson, Jeannette M, Jones, Gareth A, Kew, James NC, Pemberton, Darrel J, Murkitt, Graham S, Cato, Katherine J, Davies, Ceri H, Southam, Eric, Foxton, Richard, Gartlon, Jane

2008

Overview

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.

• Publisher: Springer International Publishing,Nature Publishing Group
• Subject: Animals / Behavioral Sciences / Biological Psychology / Brain - cytology / Brain - drug effects / Calcium - metabolism / Cell Line, Transformed / Cell Line, Tumor / Dopamine - metabolism / Dose-Response Relationship, Drug / Guinea Pigs / Humans / In Vitro Techniques / Male / Medicine / Medicine & Public Health / Neurons - drug effects / Neurosciences / Neurotransmitter Agents - metabolism / original-article / Pharmacotherapy / Protein Binding - drug effects / Psychiatry / Quinolines - pharmacology / Receptors, Neurokinin-3 - antagonists & inhibitors / Receptors, Neurokinin-3 - drug effects / Receptors, Neurokinin-3 - metabolism