General Pharmacological Profile of the Novel Muscarinic Receptor Agonist SNI-2011, a Drug for Xerostomia in Sjögren’s Syndrome

A novel muscarinic receptor agonist SNI-2011 ((±)-cis-2-methylspiro[1,3-oxathiolane-5,3’-quinuclidine] monohydrochloride hemihydrate, cevimeline, CAS 153504-70-2), is a candidate therapeutic drug for xerostomia in Sjogren’s syndrome. The general pharmacological properties of this drug on the somatic nervous system and on the autonomic nervous system and smooth muscle were investigated in mice, rats, guinea pigs, rabbits and cats. 1. Somatic nervous system: SNI-2011 had no effect on the neuromuscular junction in rats and no muscle relaxant effect in mice. No surface anesthetic effect was observed in guinea pigs, but infiltration anesthetic effect was found after intracutaneous injection of solution (1 % or higher). 2. Autonomic nervous system and smooth muscle: SNI-2011 tended to cause mydriasis at 3 mg/kg i.v. or higher in rabbits and dose-dependently caused mydriasis at 10 mg/kg p.o. or higher in rats. Mydriasis in rats was also observed by ophthalmic instillation, caused via the peripheral muscarinic acetylcholine receptors. SNI-2011 elevated the base line tension of nictitating membrane in cats when it was injected intravenously at 3 mg/kg or higher. In the smooth muscle, SNI-2011 increased the spontaneous movement of isolated rabbit ileum (1 ×10 −6 mol/l or higher), contractions of isolated guinea pig ileum (1 × 10 −6 mol/l or higher) and isolated guinea pig trachea (3 × 10 −6 mol/l or higher). SNI-2011 relaxed the histamine- and noradrenalineinduced contractions of isolated guinea pig aorta and augmented noradrenalineand phenylephrine-induced contractions of isolated rat vas deferens. These effects were induced by relatively higher concentrations only i.e. 1 × 10 −5 mol/l or higher. From these results, SNI-2011 has muscarinic side effects on the somatic nervous system and on the autonomic nervous system and smooth muscle, however, in the case of oral administration, that is clinical administration route, SNI-2011 caused no muscarinic side effect at the effective doses needed for saliva secretion.