Characterization of a new muscarinic receptor antagonist PNU-171990 in guinea pig, cat and human smooth muscle.
The present study was done to characterize a new compound, PNU-171990, 2-diisopropyl aminoethyl 1-phenylcyclopentane carboxylate hydrochloride, with functional smooth muscle selectivity at least as high as tolterodine. In vitro homogenates of guinea pig cerebral cortex, parotid gland, heart, urinary bladder, and Chinese hamster ovary (CHO) cells expressing human muscarinic m(1)-m(5) receptors PNU-171990 did not show selectivity for any subtype (pK(i), 7.72-8.64). PNU-171990 caused a parallel shift in the concentration-response curve for carbachol-induced contraction of smooth muscle from guinea pig bladder (pK(B), 7.65), guinea pig ileum (pK(B), 8.48), and human ileum (pK(B), 7.10). In vivo PNU-171990 inhibited urinary bladder contraction with a significantly lower ID(50) than on the salivary secretion (206 and 706 nmol/kg, respectively, P<0.05). In conclusion, PNU-171990 is a competitive and potent muscarinic receptor antagonist in vitro with a numerically better selectivity ratio for the bladder contraction over salivation in vivo than tolterodine.
Modiri
Ali-Reza
AR
Department of Biology, Biovitrum, UF5-1, SE-751 37, Uppsala, Sweden. ali-reza.modiri@biovitrum.com
Vasänge
Mervi
M
Alberts
Peteris
P
Jossan
Sukhwinder S
SS
Sundquist
Staffan
S
Gillberg
Per-Göran
PG
D000328:Adult; D000818:Animals; D016466:CHO Cells; D002264:Carboxylic Acids; D002415:Cats; D006224:Cricetinae; D003521:Cyclopropanes; D004305:Dose-Response Relationship, Drug; D004952:Esters / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D005260:Female; D006168:Guinea Pigs; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D008875:Middle Aged; D018727:Muscarinic Antagonists / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D009119:Muscle Contraction / Q000187:drug effects / Q000502:physiology; D009130:Muscle, Smooth / Q000187:drug effects* / Q000378:metabolism; D011976:Receptors, Muscarinic / Q000378:metabolism*
C472005:2-(diisopropylamino)ethyl 1-phenylcyclopentanecarboxylate; D002264:Carboxylic Acids; D003521:Cyclopropanes; D004952:Esters; D018727:Muscarinic Antagonists; D011976:Receptors, Muscarinic