Background and purpose: Highly selective M 3 muscarinic receptor antagonists may represent a better treatment for overactive bladder syndrome, diminishing side effects. Cardiac side effects of non‐selective antimuscarinics have been associated with activity at M 2 receptors as these receptors are mainly responsible for muscarinic receptor‐dependent bradycardia. We have investigated a novel antimuscarinic, SVT‐40776, highly selective for M 3 over M 2 receptors (Ki = 0.19 nmol·L −1 for M 3 receptor affinity). This study reports the functional activity of SVT‐40776 in the bladder, relative to its activity in atria. Experimental approach: In vitro and ex vivo (oral dosing) inhibition of mouse detrusor and atrial contractile responses to carbachol were used to study the functional activity of SVT‐40776. The in vivo efficacy of SVT‐40776 was characterized by suppression of isovolumetric spontaneous bladder contractions in anaesthetized guinea pigs after intravenous administration. Key results: SVT‐40776 was the most potent in inhibiting carbachol‐induced bladder contractions of the anti‐cholinergic agents tested, without affecting atrial contractions over the same range of concentrations. SVT‐40776 exhibited the highest urinary versus cardiac selectivity (199‐fold). In the guinea pig in vivo model, SVT‐40776 inhibited 25% of spontaneous bladder contractions at a very low dose (6.97 µg·kg −1 i.v), without affecting arterial blood pressure. Conclusions and implications: SVT‐40776 is a potent inhibitor of M 3 receptor‐related detrusor contractile activity. The absence of effects on isolated atria preparations represents an interesting characteristic and suggests that SVT‐40776 may lack unwanted cardiac effects; a feature especially relevant in a compound intended to treat mainly elderly patients. British Journal of Pharmacology (2009) doi:10.1111/j.1476‐5381.2008.00082.x

CNS Drug ReviewsVolume 4, Issue 3 p. 201-224 Free Access E-5842: A New Potent and Preferential Sigma Ligand. Preclinical Pharmacological Profile X. Guitart*, Corresponding Author X. Guitart* Neuropharmacology Department, Research Center, Laboratorio Esteve S. A., Barcelona, SpainDr. X. Guitart, Dept. Neuropharmacology, Research Center, Laboratorio Esteve S. A., Verge de Montserrat, 221. Barcelona, E-08041, Spain. Fax: +34-93-450-1611.Search for more papers by this authorX. Codony, X. Codony Neuropharmacology Department, Research Center, Laboratorio Esteve S. A., Barcelona, SpainSearch for more papers by this authorM. Ballarín, M. Ballarín Neuropharmacology Department, Research Center, Laboratorio Esteve S. A., Barcelona, SpainSearch for more papers by this authorA. Dordal, A. Dordal Neuropharmacology Department, Research Center, Laboratorio Esteve S. A., Barcelona, SpainSearch for more papers by this authorA. J. Farré, A. J. Farré Neuropharmacology Department, Research Center, Laboratorio Esteve S. A., Barcelona, SpainSearch for more papers by this author X. Guitart*, Corresponding Author X. Guitart* Neuropharmacology Department, Research Center, Laboratorio Esteve S. A., Barcelona, SpainDr. X. Guitart, Dept. Neuropharmacology, Research Center, Laboratorio Esteve S. A., Verge de Montserrat, 221. Barcelona, E-08041, Spain. Fax: +34-93-450-1611.Search for more papers by this authorX. Codony, X. Codony Neuropharmacology Department, Research Center, Laboratorio Esteve S. A., Barcelona, SpainSearch for more papers by this authorM. Ballarín, M. Ballarín Neuropharmacology Department, Research Center, Laboratorio Esteve S. A., Barcelona, SpainSearch for more papers by this authorA. Dordal, A. Dordal Neuropharmacology Department, Research Center, Laboratorio Esteve S. A., Barcelona, SpainSearch for more papers by this authorA. J. Farré, A. J. Farré Neuropharmacology Department, Research Center, Laboratorio Esteve S. A., Barcelona, SpainSearch for more papers by this author First published: 07 June 2006 https://doi.org/10.1111/j.1527-3458.1998.tb00065.xCitations: 21AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat Citing Literature Volume4, Issue3September 1998Pages 201-224 ReferencesRelatedInformation

1 The involvement of presynaptic 5-hydroxytryptamine(1A) (5-HT1A) autoreceptors in the anxiolytic-like properties of lesopitron (E-4424) (2-{4-[4-(4-chloro-1-pyrazolyl)butyl]-1-piperazinyl}pyrimidine) was studied. Brain microdialysis was used to examine the effect of the drug on the release of 5-hydroxytryptamine (5-HT) and its metabolite 5-hydroxyindoleacetic acid (5-HIAA) in the frontal cortex of awake, freely moving rats. Moreover, extracellular cortical 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) were also studied to assess the possible participation of dopaminergic systems.2 Lesopitron administered at a dose which induces anxiolytic behaviour in rats (30 mu g kg(-1), i.p.) markedly reduced 5-HT levels (to 45% of the basal value) in cortical perfusates, having no effect on 5-HIAA, DOPAC and HVA. The effects of lesopitron were compared with those produced by the anxiolytic, and structurally related compound, buspirone.3 Buspirone administered at a dose inducing anxiolytic-like effects in rats (5 mg kg(-1), i.p.) produced a marked decrease in cortical 5-HT levels (to 20% of the basal value), but in contrast to lesopitron, buspirone produced a pronounced increase in cortical DOPAC (to 300% of the basal value) and HVA (to 400% of the basal value) levels. Buspirone administered at a low dose (30 mu g kg(-1), i.p.) was unable to affect cortical 5-HT levels.4 To test the hypothesis that the 5-HT decreasing effect of lesopitron could be due to 5-HT1A autoreceptor (somatodendritic)-mediated inhibition of 5-HT neurotransmission, lesopitron was administered locally into the raphe nuclei. Intraraphe administration of 10 mu M lesopitron caused a decrease in cortical 5-HT levels (the effect being of the same order as that obtained after systemic injection), with no effect on 5-HIAA, DOPAC and HVA. Raphe 5-HT extracellular levels were not modified after intraraphe administration of lesopitron, indicating the absence of 5-HT reuptake blocking properties.5 We concluded that lesopitron, at an anxiolytic dose produced a marked inhibition of 5-HT release in the frontal cortex of awake, freely moving rats. This effect was observed after systemic administration as well as after intraraphe administration of the drug, suggesting an agonistic action at raphe 5-HT1A autoreceptors controlling 5-HT release in the projecting areas. In contrast to buspirone, lesopitron treatment had no effect on cortical DOPAC or HVA levels.