Effects of TAK-637, a tachykinin receptor antagonist, on the micturition reflex in guinea pigs.
The effects of a new tachykinin NK(1) receptor antagonist, (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 (TAK-637), on the micturition reflex were compared with those of drugs used for abnormally frequent micturition or incontinence. TAK-637 showed a characteristic effect on the distension-induced rhythmic bladder contractions in guinea pigs. The systemic administration of TAK-637 decreased the number but not the amplitude of the distension-induced rhythmic bladder contractions. A similar effect was observed in animals in which the spinal cord had been severed. TAK-637 also inhibited the micturition reflex induced by topical application of capsaicin onto the surface of bladder dome. From these results, it is concluded that TAK-637 inhibits sensory transmissions from the bladder evoked by both physiological and nociceptive stimuli by blocking tachykinin NK(1) receptors, possibly at the level of the spinal cord. On the other hand, the other drugs such as oxybutynin, tolterodine, propiverine, and inaperisone showed no effects on the frequency of the distension-induced rhythmic bladder contractions but decreased the contraction amplitude. Therefore, TAK-637 may represent a new class of drugs, which would be effective for abnormally frequent micturition without causing voiding difficulties due to decreased voiding pressure.
Doi
T
T
Pharmaceutical Research Division, Takeda Chemical Industries, Ltd., 2-17-85, Jusohonmachi, Yodogawa-ku, Osaka, Japan. doi_takayuki@taleda.co.jp
Kamo
I
I
Imai
S
S
Okanishi
S
S
Ikeura
Y
Y
Natsugari
H
H
D000818:Animals; D001559:Benzhydryl Compounds / Q000494:pharmacology; D001561:Benzilates / Q000494:pharmacology; D002211:Capsaicin / Q000494:pharmacology; D018680:Cholinergic Antagonists / Q000494:pharmacology; D003408:Cresols / Q000494:pharmacology; D004106:Dilatation; D004305:Dose-Response Relationship, Drug; D006168:Guinea Pigs; D008297:Male; D008333:Mandelic Acids / Q000494:pharmacology; D018727:Muscarinic Antagonists / Q000494:pharmacology; D009119:Muscle Contraction / Q000187:drug effects; D009125:Muscle Relaxants, Central / Q000494:pharmacology; D009287:Naphthyridines / Q000494:pharmacology*; D010276:Parasympatholytics / Q000494:pharmacology; D010665:Phenylpropanolamine; D010880:Piperidines / Q000494:pharmacology; D011427:Propiophenones / Q000494:pharmacology; D018039:Receptors, Tachykinin / Q000037:antagonists & inhibitors*; D012018:Reflex / Q000187:drug effects; D000068737:Tolterodine Tartrate; D001743:Urinary Bladder / Q000187:drug effects* / Q000294:innervation / Q000502:physiology; D014554:Urination / Q000187:drug effects*
D001559:Benzhydryl Compounds; D001561:Benzilates; D018680:Cholinergic Antagonists; D003408:Cresols; D008333:Mandelic Acids; D018727:Muscarinic Antagonists; D009125:Muscle Relaxants, Central; D009287:Naphthyridines; D010276:Parasympatholytics; D010880:Piperidines; D011427:Propiophenones; D018039:Receptors, Tachykinin; C052425:inaperisone; C080755:3-(2-methoxybenzylamino)-2-phenylpiperidine; D010665:Phenylpropanolamine; C015586:propiverine; D000068737:Tolterodine Tartrate; C005419:oxybutynin; C403052:TAK 637; D002211:Capsaicin