title: In vitro and in vivo comparison of two non-peptide tachykinin NK3 receptor antagonists: Improvements in efficacy achieved through enhanced brain penetration or altered pharmacological characteristics.
abstract: Clinical evaluation of tachykinin NK(3) receptor antagonists has provided support for the therapeutic utility of this target in schizophrenia. However, these studies have not been entirely conclusive, possibly because of the pharmacokinetic limitations of these molecules. In the search for tachykinin NK(3) receptor antagonists with improved properties, we have discovered GSK172981 and GSK256471. Both compounds demonstrated high affinity for recombinant human (pK(i) values 7.7 and 8.9, respectively) and native guinea pig (pK(i) values 7.8 and 8.4, respectively) tachykinin NK(3) receptors. In vitro functional evaluations revealed GSK172981 to be a competitive antagonist (pA(2)=7.2) at cloned human tachykinin NK(3) receptor whereas GSK256471 diminished the neurokinin B-induced E(max) response, indicative of non-surmountable antagonist pharmacology (pA(2)=9.2). GSK172981 also exhibited a competitive profile in antagonizing neurokinin B-stimulated neuronal activity recorded from the guinea pig medial habenula slices (apparent pK(B)=8.1), whilst GSK256471 abolished the agonist-induced response. Central nervous system penetration by GSK172981 and GSK256471 was indicated by dose-dependent ex vivo tachykinin NK(3) receptor occupancy in medial prefrontal cortex (ED(50) values of 0.8 and 0.9 mg/kg, i.p., respectively) and the dose-dependent attenuation of agonist-induced "wet dog shake" behaviours in guinea pigs. Finally, in vivo microdialysis studies demonstrated that acute GSK172981 (30 mg/kg, i.p.) and GSK256471 (1mg/kg, i.p.) attenuated haloperidol-induced increases in extracellular dopamine in the guinea pig nucleus accumbens. Taken together, these in vitro and in vivo characterisations of the tachykinin NK(3) receptor antagonists GSK172981 and GSK256471 support their potential utility in the treatment of schizophrenia.
authors.affiliation: Neurosciences Centre of Excellence for Drug Discovery, GlaxoSmithKline, New Frontiers Science Park, Harlow, Essex, UK. Lee_Dawson@eisai.net
authors.forename: Lee A
authors.initials: LA
authors.lastname: Dawson
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Langmead
authors.forename: Adeshola
authors.initials: A
authors.lastname: Dada
authors.forename: Jeannette M
authors.initials: JM
authors.lastname: Watson
authors.forename: Zining
authors.initials: Z
authors.lastname: Wu
authors.forename: Raúl
authors.initials: R
authors.lastname: de la Flor
authors.forename: Gareth A
authors.initials: GA
authors.lastname: Jones
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: Mark D
authors.initials: MD
authors.lastname: Hill
authors.forename: Declan N C
authors.initials: DN
authors.lastname: Jones
authors.forename: Ceri H
authors.initials: CH
authors.lastname: Davies
authors.forename: Jim J
authors.initials: JJ
authors.lastname: Hagan
authors.forename: Paul W
authors.initials: PW
authors.lastname: Smith
mesh_terms: D000634:Aminoquinolines / Q000378:metabolism* / Q000493:pharmacokinetics / Q000494:pharmacology*; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D001921:Brain / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism* / Q000502:physiology; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism; D003001:Cloning, Molecular; D004298:Dopamine / Q000378:metabolism; D005110:Extracellular Space / Q000187:drug effects / Q000378:metabolism; D006168:Guinea Pigs; D019262:Habenula / Q000166:cytology; D006220:Haloperidol / Q000494:pharmacology; D006801:Humans; D007295:Inositol Phosphates / Q000378:metabolism; D008297:Male; D017551:Microdialysis; D015287:Neurokinin B / Q000494:pharmacology; D009474:Neurons / Q000166:cytology / Q000187:drug effects; D009714:Nucleus Accumbens / Q000187:drug effects / Q000378:metabolism; D010446:Peptide Fragments / Q000494:pharmacology; D010455:Peptides / Q000737:chemistry; D011804:Quinolines / Q000378:metabolism* / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D018039:Receptors, Tachykinin / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D013373:Substance P / Q000031:analogs & derivatives / Q000494:pharmacology
chemical_list: C548347:3-amino-N-(cyclopropyl (phenyl)methyl)-2-(3-fluorophenyl)-4-quinolinecarboxamide; D000634:Aminoquinolines; C539893:GSK256471; D007295:Inositol Phosphates; D010446:Peptide Fragments; D010455:Peptides; D011804:Quinolines; D018039:Receptors, Tachykinin; C054724:senktide; D013373:Substance P; D015287:Neurokinin B; D006220:Haloperidol; D004298:Dopamine