In vivo and in vitro pharmacological characterization of SVT-40776, a novel M(3) muscarinic receptor antagonist, for the treatment of overactive bladder. British journal of pharmacology [Br J Pharmacol] Journal article | | Title | In vivo and in vitro pharmacological characterization of SVT-40776, a novel M(3) muscarinic receptor antagonist, for the treatment of overactive bladder. | | Author(s) | Salcedo C, Davalillo S, Cabellos J, Lagunas C, Balsa D, Pérez-Del-Pulgar S, Ballarín M, Fernández A | | Institution | Present address: Drug Development & Clinical Research, Palau Pharma S.A. Avinguda Camí Reial 51-57, 08184 Palau Solità i Plegamans, Barcelona, Spain. | | Source | Br J Pharmacol 2009 Feb 16. | | Abstract | 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 microg.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. | | Language | ENG | | Pub Type(s) | JOURNAL ARTICLE
| | PubMed ID | 19222482 |
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