Jpn. J. Pharmacol. 78 (3), 373-380 (1998)

(+/-)-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

Yoshinori Iga, Hirohiko Arisawa, Nobuo Ogane, Yasunari Saito, Toshie Tomizuka, Yuzo Nakagawa-Yagi, Hiroaki Masunaga, Hiroshi Yasuda and Nobuo Miyata

Research Institute of Life Science, Snow Brand Milk Products Co., Ltd., 519, Shimo-ishibashi, Ishibashi-machi, Shimotsuga-gun, Tochigi 329-0512, Japan

Abstract: 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 Sjogren's syndrome and X-ray exposure in the head and neck.

Keywords: SNI-2011, Muscarinic agonist, Sjogren's syndrome, Salivary gland, Lacrimal gland

Copyrightę The Japanese Pharmacological Society 1998

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