Neurokinin 1 Receptor Antagonists: Correlation between in Vitro Receptor Interaction and in Vivo Efficacy

• DOI: 10.1124/jpet.107.124958
• Publication Date: 2007-06-16T13:26:17Z
• Authors: Erik Lindström; Bengt von Mentzer; Ingrid Påhlman; Ingela Ahlstedt; Anna Uvebrant; Elin Kristensson; Rakel Martinsson; Anna Novén; Jennie de Verdier; Georges Vauquelin
• Keywords: Aprepitant; Gerbil; Tachykinin receptor 1

We compared the neurokinin 1 receptor (NK₁R) antagonists aprepitant, CP-99994 [(2<i>S</i>,3<i>S</i>)-3-(2-methoxybenzylamino)-2-phenylpiperidine], and ZD6021 [3-cyano-<i>N</i>-((2<i>S</i>)-2-(3,4-dichlorophenyl)-4-[4-[2-(methyl-(<i>S</i>)-sulfinyl)phenyl]piperidino]butyl)-<i>N</i>-methyl]napthamide]] with respect to interactions duration of efficacy in vivo. In Ca²⁺ mobilization assays (fluorometric imaging plate reader), were applied human U373MG cells simultaneously or 2.5 min before substance P (SP). reversibility studies, present for 30 washing, responses SP repeatedly measured afterward. The compounds administered i.p. gerbils, gerbil foot tap (GFT) response was monitored at various time points. NK₁R occupancy aprepitant determined striatal regions. Levels compound brain plasma measured. Antagonists equipotent acted competitively SP. After preincubation, attenuated maximal responses, whereas only shifted concentration-response curve right. inhibitory effect over within min, ZD6021, 50% inhibition still persisted after 60 min. Aprepitant produced lasting least (3 μmol/kg) inhibited GFT by 100% 15 administration, but declined rapidly together levels thereafter. (10 lasted 4 h correlated well levels. occupied &gt;48 despite that below limit detection 24 h. Slow functional is associated long-lasting vivo antagonists, rapid reflected their pharmacokinetics.