We investigated effects of (+/-)-cis-2-methylspiro[1,3-oxathiolane-5,3'-quinuclidine] hydrochloride, hemihydrate (SNI-2011, cevimeline hydrochloride), a rigid analogue of acetylcholine, on saliva and tear secretions in rats and mice to evaluate its therapeutical efficacy for xerostomia and xerophthalmia in patients with Sjogren's syndrome and X-ray exposure in the head and neck. Intraduodenal administrations of SNI-2011 increased saliva secretion in a dose-dependent manner at doses ranging from 3 to 30 mg/kg in normal rats and mice, two strains of autoimmune disease mice and X-irradiated saliva secretion defective rats. The salivation elicited by SNI-2011 was completely inhibited by atropine. A similar atropine-sensitive response was observed in tear secretion. In rat submandibular/sublingual gland membranes, [3H]quinuclidinyl benzilate (QNB) binding was saturable, and Scatchard plot analysis revealed a single population of binding sites with a Kd of 22 pM and a maximal binding capacity of 60 fmol/mg protein. The competitive inhibition curve of the [3H]QNB binding by SNI-2011 was obtained, and its dissociation constant value calculated from IC50 was 1-2 microM. These results suggest that SNI-2011 increases saliva and tear secretions through a direct stimulation to muscarinic receptors in salivary and lacrimal glands, and they suggest that SNI-2011 should be beneficial to patients with Sjögren's syndrome and X-ray exposure in the head and neck.
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 Sjögren's syndrome. The general pharmacological properties of this drug on general behavior and the central nervous system were investigated in mice, rats and cats. 1. General behavior: When SNI-2011 was administered orally to mice at 100 mg/kg, mydriasis, a decrease of spontaneous motor activity, tremor, convulsions, salivation, abnormal posture, abnormal gait, reduced grip strength and reduced response against external stimulating were observed, and 2 out of 6 animals died. At 10 mg/kg or lower, no particular sign was observed except mydriasis, which appeared to be caused via the peripheral muscarinic acetylcholine receptors. 2. Central nervous system: SNI-2011 had no effect on the motor coordination in mice. Hypothermia was observed in rats and reduced spontaneous motor activity, analgesia and enhanced maximum electroshock-induced convulsions were observed in mice after oral administration of 30 mg/kg SNI-2011. Slight increase in the rate of theta-wave band in the hippocampal EEG of rats and spinal multisynaptic reflexes in cats were observed after intravenous injection of 10 mg/kg SNI-2011. At an oral dose of 10 mg/kg, prolongation of thiopental-induced sleeping time in mice was observed. The prolongation of sleeping time was inhibited by a peripheral muscarinic antagonist. These results suggest that SNI-2011 has muscarinic effects on general behavior and the central nervous system at the doses approximately 10-fold higher than the effective doses needed for saliva secretion.
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