title: In vitro and in vivo characterization of the non-peptide NK3 receptor antagonist SB-223412 (talnetant): potential therapeutic utility in the treatment of schizophrenia.
abstract: 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.
authors.affiliation: Psychiatry Centre of Excellence for Drug Discovery, GlaxoSmithKline, Essex, UK. Lee.A.Dawson@gsk.com
authors.forename: Lee A
authors.initials: LA
authors.lastname: Dawson
authors.forename: Katherine J
authors.initials: KJ
authors.lastname: Cato
authors.forename: Claire
authors.initials: C
authors.lastname: Scott
authors.forename: Jeannette M
authors.initials: JM
authors.lastname: Watson
authors.forename: Martyn D
authors.initials: MD
authors.lastname: Wood
authors.forename: Richard
authors.initials: R
authors.lastname: Foxton
authors.forename: Raúl
authors.initials: R
authors.lastname: de la Flor
authors.forename: Gareth A
authors.initials: GA
authors.lastname: Jones
authors.forename: James Nc
authors.initials: JN
authors.lastname: Kew
authors.forename: Jane E
authors.initials: JE
authors.lastname: Cluderay
authors.forename: Eric
authors.initials: E
authors.lastname: Southam
authors.forename: Graham S
authors.initials: GS
authors.lastname: Murkitt
authors.forename: Jane
authors.initials: J
authors.lastname: Gartlon
authors.forename: Darrel J
authors.initials: DJ
authors.lastname: Pemberton
authors.forename: Declan Nc
authors.initials: DN
authors.lastname: Jones
authors.forename: Ceri H
authors.initials: CH
authors.lastname: Davies
authors.forename: Jim
authors.initials: J
authors.lastname: Hagan
mesh_terms: D000818:Animals; D001921:Brain / Q000166:cytology / Q000187:drug effects*; D002118:Calcium / Q000378:metabolism; D002461:Cell Line, Transformed; D045744:Cell Line, Tumor; D004298:Dopamine / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D006168:Guinea Pigs; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D009474:Neurons / Q000187:drug effects; D018377:Neurotransmitter Agents / Q000378:metabolism; D011485:Protein Binding / Q000187:drug effects; D011804:Quinolines / Q000494:pharmacology*; D018042:Receptors, Neurokinin-3 / Q000037:antagonists & inhibitors* / Q000187:drug effects / Q000378:metabolism
chemical_list: D018377:Neurotransmitter Agents; D011804:Quinolines; D018042:Receptors, Neurokinin-3; C106716:SB 223412; D002118:Calcium; D004298:Dopamine