Received for publication May 3, 2007.
Revised June 14, 2007.
Accepted for publication June 14, 2007.

Neurokinin (NK)1 receptor antagonists: Correlation between in vitro receptor interaction and in vivo efficacy

Abstract

We compared the neurokinin 1 receptor (NK₁R) antagonists aprepitant, CP99,994 and ZD6021 with respect to receptor interactions and duration of efficacy in vivo. In Ca²⁺ mobilization assays (FLIPR), antagonists were applied to human U373MG cells simultaneously with or 2.5 min before substance P (SP). In reversibility studies, antagonists were present for 30 min before washing and responses to SP were repeatedly measured afterwards. The compounds were administered i.p. to gerbils and the gerbil foot tap (GFT) response was monitored at various time points. The NK₁R receptor occupancy for aprepitant was determined in striatal regions. Levels of compound in brain and plasma were measured. Antagonists were equipotent at human NK₁R and acted competitively with SP. After pre-incubation, aprepitant and ZD6021 attenuated the maximal responses, while CP99,994 only shifted the SP concentration-response curve to the right. The inhibitory effect of CP99,994 was over within 30 min while for ZD6021, 50% inhibition still persisted after 60 min. Aprepitant produced maximal inhibition lasting at least 60 min. CP99,994 (3 µmol/kg) inhibited GFT by 100% 15 min after administration but the effect declined rapidly together with brain levels thereafter. The efficacy of ZD6021 (10 µmol/kg) lasted 4h and correlated well with brain levels. Aprepitant (3 µmol/kg) inhibited GFT and occupied striatal NK₁R by 100% for >48h despite brain levels of compound were below the limit of detection after 24h. Slow functional reversibility is associated with long-lasting in vivo efficacy of NK₁R antagonists while the efficacy of compounds with rapid reversibility is reflected by their pharmacokinetics.

Key words: Insurmountable, Neurokinin 1 receptors, competitive, gerbil foot tap, long-lasting effect, reversibility

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