YM-44778

The radioligand binding profiles and in vivo pharmacological characteristics of YM-44781, YM-44778 and YM-49598, novel non-peptide tachykinin receptor antagonists, were examined and compared to those of FK-888 and GR-159897. Since no functional NK₃ receptors were found in the rat bladder, the emphasis will be on the other two subtypes. YM-44781 and YM-49598 exhibited high binding affinities at NK₂ (pK_i = 9.94 ± 0.03) and NK₁ (pK_i = 9.09 ± 0.02) receptors, respectively, whereas YM-44778 exhibited high binding affinities at both NK₁ (pK_i = 8.08 ± 0.07) and NK₂ (pK_i = 8.55 + 0.04) receptors stably transfected in CHO-K1 cells (Chinese hamster ovary cells). In an in vivo rat model, a drug-induced bladder contraction model, antagonism of the contractions produced by the selective NK₂ receptor agonist, [βAla⁸]neurokinin A (4–10) (10 µg·kg^–1 i.v.) was observed after intravenous administration (dose range 0.001–1 mg·kg^–1) of YM-44781 and YM-44778 (IC₅₀ = 27 ± 8 and 100 ± 44 µg· kg^–1, respectively). YM-44781 was more potent (about 3-fold) than YM-44778. YM-49598 was almost inactive but produced a potent inhibition (IC₅₀ = 11 ± 7 µg·kg^–1) of the contraction of the rat urinary bladder induced by challenge with the NK₁-selective receptor agonist [Sar⁹,Met(O₂)¹¹]substance P sulphone (0.3 µg·kg^–1). YM-44781 and YM-44778 did not produce major inhibition of [Sar⁹,Met(O₂)¹¹]substance P-induced bladder contraction. These findings indicate that YM-44781 and YM-49598 are potent NK₂ and NK₁ receptor antagonists, respectively, whereas YM-44778 is a nonselective NK₂/NK₁ receptor antagonist in the drug-induced bladder contraction model.

To discover a novel NK1-NK2 dual antagonist, we have synthesized a series of spiro-substituted piperidines utilizing YM-35375 as a lead compound, and evaluated affinities for NK1 and NK2 receptors. In the N-methylbenzamide moiety, introduction of methoxy groups increased affinity for the NK1 receptor without a significant loss of affinity for the NK2 receptor. We also found that a conformation in which the phenyl groups of the N-methylbenzamide and 3,4-dichlorophenyl moieties are close to each other through a cis-amide bond, may be favorable for showing high affinity for the NK1 receptor and that a hydrogen bond-accepting group in the spiro-substituted piperidine moiety may be crucial for exhibiting high affinity for the NK2 receptor. Among the compounds prepared, YM-44778 (31) showed high and well-balanced affinity for NK1 and NK2 receptors (IC50 values of 18 and 16 nM, respectively). This compound also exhibited potent antagonistic activities against both NK1 and NK2 receptors (IC50 values of 82 and 62 nM, respectively) in isolated tissues.