Effects of TAK-637, a tachykinin receptor antagonist, on lower urinary tract function in the guinea pig.
The effects of TAK-637 ((aR,9R)-7-[3,5-bis(trifluoromethyl)benzyl]-8, 9,10,11-tetrahydro-9-methyl-5-(4-methylphenyl)-7H-[1,4]diazocino[2 , 1-g][1,7]naphthyridine-6,13-dione), a novel tachykinin NK(1) receptor antagonist, on the micturition reflex in guinea pigs were studied in comparison with those of anti-pollakiuria agents. Cystometry was performed under urethane anesthesia. TAK-637 increased the volume threshold with a minimum effective dose of 0.03 mg/kg, i.v. without affecting voiding pressure. Oxybutynin, tolterodine, propiverine and inaperisone also increased the volume threshold in urethane-anesthetized guinea pigs, but they decreased voiding pressure, although the effect of propiverine was not statistically significant. A structurally unique tachykinin NK(1) receptor antagonist, (+/-)-CP-99,994 ((+/-)-(2S, 3S)-3-(2-methoxybenzylamino)-2-phenylpiperidine), increased the volume threshold with a minimum effective dose of 0.3 mg/kg, i.v. TAK-637 increased the volume threshold with a minimum effective dose of 0.01 mg/kg, p.o. in unanesthetized guinea pigs. These results indicate that TAK-637 may be useful as pharmacotherapy for detrusor overactivity without decreasing voiding pressure or causing voiding difficulties.
Doi
T
T
Pharmaceutical Research Division, Takeda Chemical Industries, 2-17-85, Jusohonmachi, Yodogawa-ku, Osaka, Japan. Doi Takayuki@takeda.co.jp
Kamo
I
I
Imai
S
S
Okanishi
S
S
Ishimaru
T
T
Ikeura
Y
Y
Natsugari
H
H
D000818:Animals; D004121:Dimethyl Sulfoxide / Q000494:pharmacology; D006168:Guinea Pigs; D008297:Male; D009287:Naphthyridines / Q000494:pharmacology*; D010880:Piperidines / Q000494:pharmacology; D011312:Pressure; D018039:Receptors, Tachykinin / Q000037:antagonists & inhibitors*; D012018:Reflex / Q000187:drug effects* / Q000502:physiology; D013237:Stereoisomerism; D014521:Urethra / Q000187:drug effects / Q000502:physiology; D001743:Urinary Bladder / Q000187:drug effects* / Q000502:physiology; D014554:Urination / Q000187:drug effects* / Q000502:physiology
D009287:Naphthyridines; D010880:Piperidines; D018039:Receptors, Tachykinin; C080755:3-(2-methoxybenzylamino)-2-phenylpiperidine; C403052:TAK 637; D004121:Dimethyl Sulfoxide