Effect of YM-44781, YM-44778 and YM-49598, Novel Tachykinin Antagonists, in a Drug-Induced Bladder Contraction Model

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 NK 3 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 NK 2 (pK i = 9.94 ± 0.03) and NK 1 (pK i = 9.09 ± 0.02) receptors, respectively, whereas YM-44778 exhibited high binding affinities at both NK 1 (pK i = 8.08 ± 0.07) and NK 2 (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 NK 2 receptor agonist, [βAla 8 ]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 (IC 50 = 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 (IC 50 = 11 ± 7 µg·kg –1 ) of the contraction of the rat urinary bladder induced by challenge with the NK 1 -selective receptor agonist [Sar 9 ,Met(O 2 ) 11 ]substance P sulphone (0.3 µg·kg –1 ). YM-44781 and YM-44778 did not produce major inhibition of [Sar 9 ,Met(O 2 ) 11 ]substance P-induced bladder contraction. These findings indicate that YM-44781 and YM-49598 are potent NK 2 and NK 1 receptor antagonists, respectively, whereas YM-44778 is a nonselective NK 2 /NK 1 receptor antagonist in the drug-induced bladder contraction model.