Characterization of NK3 Receptors in Rabbit Eye: Insights from In Vitro and In Vivo Studies with Selective Antagonists

The study investigates the efficacy of three novel 2-phenyl-4-quinolinecarboxamides as non-peptide NK3 receptor antagonists, focusing on their in vitro and in vivo functionality. These compounds were evaluated for their ability to inhibit contractions in the rabbit isolated iris sphincter muscle induced by NK3 receptor agonists. Additionally, the in vivo effect of these agonists, which cause miosis in conscious rabbits, was studied alongside the antagonists.

In the in vitro setting, senktide and [MePhe7]-NKB demonstrated potent contractile effects on the rabbit iris sphincter muscle, but with different concentration-effect profiles. The antagonists SB 223412, SB 222200, and SB 218795 effectively antagonized the contractile responses to senktide in a concentration-dependent manner, indicating their potency and selectivity for the NK3 receptor.

SB 218795 did not affect the contractile responses to [MePhe7]-NKB, while SB 223412 and SB 222200 showed inhibition, particularly at lower concentrations of the agonist. The presence of these antagonists also altered the concentration-effect curves for [MePhe7]-NKB, making them steeper and more monophasic.

In terms of selectivity, SB 218795 had no impact on contractions induced by other stimuli, such as transmural nerve stimulation or substance P, highlighting the specificity of the antagonists for NK3 receptors over NK1 receptors.

In vivo, senktide induced miosis in a concentration-dependent manner, with the effects being inhibited by the antagonists SB 222200, SB 223412, SB 218795, and the distinct NK3 receptor antagonist SR 142801. Topical administration of senktide resulted in unilateral miosis, and the response was not affected by topically administered atropine.

[MePhe7]-NKB, while less potent than senktide in the in vivo setting, also induced miosis, and its effects were inhibited by SB 222200. The study concludes that the NK3 receptor agonist-induced miosis in rabbits serves as a relevant in vivo model for evaluating the pharmacodynamics and efficacy of NK3 receptor antagonists, such as SB 222200, SB 223412, SB 218795, and SR 142801.