title: 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.
authors.affiliation: Neurobiology Unit, Roche Bioscience, Palo Alto, Calif 94025, USA. Achoppin@Deltagen.com
authors.forename: Agnes
authors.initials: A
authors.lastname: Choppin
authors.forename: Gretchen
authors.initials: G
authors.lastname: Groke
authors.forename: Analyn
authors.initials: A
authors.lastname: Bringas
authors.forename: George
authors.initials: G
authors.lastname: Stepan
authors.forename: Michael P
authors.initials: MP
authors.lastname: Dillon
mesh_terms: D000818:Animals; D001667:Binding, Competitive; D016466:CHO Cells; D006224:Cricetinae; D004151:Dipeptides / Q000378:metabolism / Q000494:pharmacology; D005260:Female; D007211:Indoles / Q000378:metabolism / Q000494:pharmacology; D009119:Muscle Contraction / Q000187:drug effects*; D015288:Neurokinin A / Q000031:analogs & derivatives* / Q000494:pharmacology*; D064729:Neurokinin-1 Receptor Antagonists; D010446:Peptide Fragments / Q000494:pharmacology*; D010880:Piperidines / Q000378:metabolism / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D018040:Receptors, Neurokinin-1 / Q000235:genetics / Q000378:metabolism; D018041:Receptors, Neurokinin-2 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D018042:Receptors, Neurokinin-3 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D018039:Receptors, Tachykinin / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013141:Spiro Compounds / Q000378:metabolism / Q000494:pharmacology; D014162:Transfection; D001743:Urinary Bladder / Q000187:drug effects* / Q000502:physiology
chemical_list: D004151:Dipeptides; C092990:GR 159897; D007211:Indoles; D064729:Neurokinin-1 Receptor Antagonists; D010446:Peptide Fragments; D010880:Piperidines; D018040:Receptors, Neurokinin-1; D018041:Receptors, Neurokinin-2; D018042:Receptors, Neurokinin-3; D018039:Receptors, Tachykinin; D013141:Spiro Compounds; C464853:YM-44778; C464852:YM-44781; C464851:YM-49598; C064218:neurokinin A (4-10), beta-Ala(8)-; C078949:FK 888; D015288:Neurokinin A