The preparation and human muscarinic receptor profiling of oxybutynin and N-desethyloxybutynin enantiomers.
Oxybutynin (1) is a non-selective muscarinic receptor antagonist that is used clinically for the treatment of urinary incontinence. The major metabolite of oxybutynin in humans is desethyloxybutynin (2). We have prepared the enantiomers of 1 and 2 and evaluated their ability to displace N-CT(3)-scopolamine chloride ((3)H-NMS) binding on human cloned muscarinic m1-5 receptors. Compounds 1 and 2 potently displaced (3)H-NMS binding at m1, m3 and m4 receptors, but were less potent at the m2 and m5 subtypes. However, metabolite 2 was more potent than the parent compound 1 in the binding assay. In general the R enantiomers were more potent than their respective S enantiomers. Therefore, we suggest that the cholinergic side effects associated with 2 may be due to its greater apparent potency with m1 and m3 receptors, especially of its R-enantiomer, when compared with parent drug 1.
Reitz
Allen B
AB
Johnson & Johnson Pharmaceutical Research and Development, Welsh & McKean Rds., Spring House, PA 19477, USA. AReitz@PRDUS.JNJ.COM
Gupta
Suneel K
SK
Huang
Yifang
Y
Parker
Michael H
MH
Ryan
Richard R
RR
D006801:Humans; D008333:Mandelic Acids / Q000737:chemistry* / Q000494:pharmacology; D018727:Muscarinic Antagonists / Q000138:chemical synthesis* / Q000494:pharmacology; D043643:Receptor, Muscarinic M1; D043585:Receptor, Muscarinic M2; D043587:Receptor, Muscarinic M3; D043588:Receptor, Muscarinic M4; D043642:Receptor, Muscarinic M5; D011976:Receptors, Muscarinic / Q000187:drug effects*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014549:Urinary Incontinence / Q000188:drug therapy
D008333:Mandelic Acids; D018727:Muscarinic Antagonists; D043643:Receptor, Muscarinic M1; D043585:Receptor, Muscarinic M2; D043587:Receptor, Muscarinic M3; D043588:Receptor, Muscarinic M4; D043642:Receptor, Muscarinic M5; D011976:Receptors, Muscarinic; C032681:desethyloxybutynin; C005419:oxybutynin