Pharmacological characterization of a new antimuscarinic agent, solifenacin succinate, in comparison with other antimuscarinic agents.
Solifenacin succinate [YM905; (3R)-1-azabicyclo[2.2.2]oct-3-yl(1S)-1-phenyl-3,4-dihydroisoquinoline-2(1H)-carboxylate monosuccinate] is a new muscarinic receptor antagonist developed for the treatment of overactive bladder. The aim of the present study was to evaluate the antimuscarinic properties of solifenacin and to compare the results with those obtained for tolterodine, oxybutynin, darifenacin, propiverine and atropine. In radioligand receptor binding assay, Ki values of solifenacin for human muscarinic M1, M2, M3, M4 and M5 receptors were 26, 170, 12, 110 and 31 nM, respectively. In isolated rat urinary bladder, solifenacin competitively antagonized carbachol-induced contractions, with a pA2 value of 7.44+/-0.09. In these in vitro studies, the antimuscarinic action of solifenacin was more potent than that of propiverine and less potent than those of tolterodine, oxybutynin, darifenacin and atropine. In anesthetized rats, solifenacin and oxybutynin increased the maximum bladder capacity in a dose-dependent manner and also decreased the maximum intravesical pressure. The dosages required to produce a 30% increase in maximum bladder capacity (ED30 values) of solifenacin and oxybutynin were 0.35 and 0.30 mg/kg i.v., respectively, indicating approximately equal efficacies. These results support the fact that solifenacin, similarly to currently used antimuscarinic agents, is an effective agent in the treatment of overactive bladder symptoms such as urinary frequency and urge incontinence.
Ohtake
Akiyoshi
A
Pharmacology Research Labs., Drug Discovery Research, Astellas Pharma Inc., Tsukuba, Ibaraki, Japan. akiyoshi.ohtake@jp.astellas.com
Saitoh
Chikashi
C
Yuyama
Hironori
H
Ukai
Masashi
M
Okutsu
Hiroko
H
Noguchi
Yukiko
Y
Hatanaka
Toshiki
T
Suzuki
Masanori
M
Sato
Shuichi
S
Sasamata
Masao
M
Miyata
Keiji
K
D000818:Animals; D001285:Atropine / Q000494:pharmacology; D001559:Benzhydryl Compounds / Q000494:pharmacology; D001561:Benzilates / Q000494:pharmacology; D001572:Benzofurans / Q000494:pharmacology; D001667:Binding, Competitive; D016466:CHO Cells; D002217:Carbachol / Q000494:pharmacology; D018679:Cholinergic Agonists / Q000494:pharmacology; D003408:Cresols / Q000494:pharmacology; D006224:Cricetinae; D003412:Cricetulus; D004305:Dose-Response Relationship, Drug; D066298:In Vitro Techniques; D008297:Male; D008333:Mandelic Acids / Q000494:pharmacology; D018727:Muscarinic Antagonists / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects; D019832:N-Methylscopolamine / Q000378:metabolism; D010665:Phenylpropanolamine / Q000494:pharmacology; D011759:Pyrrolidines / Q000494:pharmacology; D011812:Quinuclidines / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D011976:Receptors, Muscarinic / Q000187:drug effects* / Q000378:metabolism; D000069464:Solifenacin Succinate; D044005:Tetrahydroisoquinolines / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D000068737:Tolterodine Tartrate; D014162:Transfection; D001743:Urinary Bladder / Q000187:drug effects; D053201:Urinary Bladder, Overactive / Q000188:drug therapy; D014554:Urination / Q000187:drug effects
D001559:Benzhydryl Compounds; D001561:Benzilates; D001572:Benzofurans; D018679:Cholinergic Agonists; D003408:Cresols; D008333:Mandelic Acids; D018727:Muscarinic Antagonists; D011759:Pyrrolidines; D011812:Quinuclidines; D011976:Receptors, Muscarinic; D044005:Tetrahydroisoquinolines; D010665:Phenylpropanolamine; C015586:propiverine; D000068737:Tolterodine Tartrate; D001285:Atropine; D002217:Carbachol; C101207:darifenacin; C005419:oxybutynin; D000069464:Solifenacin Succinate; D019832:N-Methylscopolamine