P 7.2. Studies on the functional reversibility of antagonists active at neurokinin NK2 and NK3 neurokinin receptors

• Published in: Neuropeptides (Edinburgh) Vol. 42; no. 4; p. 493
• Main Authors: von Mentzer, B, Ahlstedt, I, Kakol-Palm, D, PAAhl-Man, I, Lindstroem, E
• Format: Journal Article
• Language: English
• Published: 01.08.2008
• ISSN: 0143-4179

Introduction and aim. We have previously demonstrated that NK1 receptor antagonists that have insurmountable interactions and slow reversibility in vitro produce long-lasting effects in vivo, while compounds with rapid reversibility in vitro produce inhibitory effects in vivo more related to metabolism of compound. The aim of the current study was to characterize the functional reversibility of antagonists active at NK2 and NK3 receptors in vitro. Methods. CHO cells were stably transfected with human recombinant NK2 and NK3 receptors. Antagonists were added at a concentration of 10 nM. After 30 min, the cells were washed with assay buffer and increases in intracellular Ca super(2+) mobilization in response to 0.15 nM NKA (NK2 receptors) or 1 nM Pro7NKB (NK3 receptors) were monitored for 60 min. Results and discussion. The selective NK2 receptor antagonist saredutant (SR48968) inhibited NKA-evoked increases in intracellular Ca super(2+) mobilization by 90-100% over 60 min. In contrast, the non-selective NK receptor antagonist ZD6021, which inhibited NKA-mediated responses by 100% for 5-10 min, retained 50% inhibition after 60 min. The selective NK3 receptor antagonist osanetant inhibited pro7NKB-evoked increases in intracellular Ca super(2+) by 90-100% over 60 min, while the inhibitory effects of other selective (talnetant) and non-selective (ZD6021) NK3 receptor antagonists appeared more short-lasting ( similar to 30 min). Conclusion. The results demonstrate that the functional reversibility of NK2 and NK3 receptor antagonists in vitro differs greatly. This may have implications for the degree and duration of inhibitory effects achievable in vivo.