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

Clinical evaluation of tachykinin NK3 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 NK3 receptor antagonists with improved properties, we have discovered GSK172981 and GSK256471. Both compounds demonstrated high affinity for recombinant human (pKi values 7.7 and 8.9, respectively) and native guinea pig (pKi values 7.8 and 8.4, respectively) tachykinin NK3 receptors. In vitro functional evaluations revealed GSK172981 to be a competitive antagonist (pA2 = 7.2) at cloned human tachykinin NK3 receptor whereas GSK256471 diminished the neurokinin B-induced Emax response, indicative of non-surmountable antagonist pharmacology (pA2 = 9.2). GSK172981 also exhibited a competitive profile in antagonizing neurokinin B-stimulated neuronal activity recorded from the guinea pig medial habenula slices (apparent pKB = 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 NK3 receptor occupancy in medial prefrontal cortex (ED50 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 (1 mg/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 NK3 receptor antagonists GSK172981 and GSK256471 support their potential utility in the treatment of schizophrenia.