(+/-)-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'-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.
Iga
Y
Y
Research Institute of Life Science, Snow Brand Milk Products Co., Ltd., Tochigi, Japan.
Arisawa
H
H
Ogane
N
N
Saito
Y
Y
Tomizuka
T
T
Nakagawa-Yagi
Y
Y
Masunaga
H
H
Yasuda
H
H
Miyata
N
N
D000818:Animals; D001667:Binding, Competitive; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005260:Female; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D018721:Muscarinic Agonists / Q000494:pharmacology; D010277:Parasympathomimetics / Q000494:pharmacology*; D011812:Quinuclidines / Q000494:pharmacology*; D011813:Quinuclidinyl Benzilate / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D011976:Receptors, Muscarinic / Q000502:physiology; D012463:Saliva / Q000187:drug effects* / Q000378:metabolism; D012469:Salivary Glands / Q000187:drug effects / Q000378:metabolism; D013666:Tears / Q000187:drug effects* / Q000378:metabolism; D013876:Thiophenes; D013997:Time Factors; D014316:Tritium
D018721:Muscarinic Agonists; D010277:Parasympathomimetics; D011812:Quinuclidines; D011976:Receptors, Muscarinic; D013876:Thiophenes; D014316:Tritium; D011813:Quinuclidinyl Benzilate; C059240:cevimeline