Effect of YM-44781, YM-44778 and YM-49598, novel tachykinin antagonists, in a drug-induced bladder contraction model

Abstract

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, [betaAla8]neurokinin A (4-10) (10 microg x kg(-1) i.v.) was observed after intravenous administration (dose range 0.001-1 mg x kg(-1)) of YM-44781 and YM-44778 (IC(50) = 27 +/- 8 and 100 +/- 44 microg x 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 microg x kg(-1)) of the contraction of the rat urinary bladder induced by challenge with the NK(1)-selective receptor agonist [Sar9,Met(O(2))11]substance P sulphone (0.3 microg x kg(-1)). YM-44781 and YM-44778 did not produce major inhibition of [Sar9,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.