(+/-)-cis-2-methylspiro[1,3-oxathiolane-5,3 '-quinuclidine]hydrochloride, hemihydrate (SNI-2011, cevimeline hydrochloride) induces saliva and tear secretions in rats and mice: The role of muscarinic acetylcholine receptors

We investigated effects of (+/-)-cis-2-methylspiro[1,3-oxathiolane-5,3'-qui nuclidine] hydrochloride, hemihydrate (SNI-2011, cevimeline hydrochloride), a rigid analogue of acetylcholine, on saliva and tear secretions in rats a nd mice to evaluate its therapeutical efficacy for xerostomia and xerophtha lmia 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 r ats and mice, two strains of autoimmune disease mice and X-irradiated saliv a secretion defective rats. The salivation elicited by SNI-2011 was complet ely inhibited by atropine. A similar atropine-sensitive response was observ ed in tear secretion. In rat submandibular/sublingual gland membranes, [H-3 ]quinuclidinyl benzilate (QNB) binding was saturable, and Scatchard plot an alysis revealed a single population of binding sites with a K-d Of 22 PM an d a maximal binding capacity of 60 fmol/mg protein. The competitive inhibit ion curve of the [H-3]QNB binding by SNI-2011 was obtained, and its dissoci ation constant value calculated from IC50 was 1-2 mu M. These results sugge st that SNI-2011 increases saliva and tear secretions through a direct stim ulation to muscarinic receptors in salivary and lacrimal glands, and they s uggest that SNI-2011 should be beneficial to patients with Sjogren's syndro me and X-ray exposure in the head and neck.