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

Abstract

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.

Cevimeline co-treatment attenuates olanzapine-induced metabolic disorders via modulating hepatic M3 muscarinic receptor: AMPKα signalling pathway in female rats

“…for treating symptoms of dry mouth (Fox and Fox, 2019), cevimeline has a much shorter half-life in rats (~2 h) than in humans (~5 ± 1 h) (FDA, 2001; Weber and Keating, 2008). The cevimeline dose used in this study has been reported without toxic effects in chronic studies up to 1 year, and without adverse effects on general behaviour, or nervous and other systems, although it may also act on other organs expressed muscarinic M3 receptors (Arisawa et al, 2002a, 2002b, 2002c; FDA, 2001; Kim et al, 2021; Weber and Keating, 2008). Body weight, food intake and water intake were measured once every week.…”

“…In addition, previous studies have reported that olanzapine treatment at lower dosages (0.5 and 1 mg/kg) also induced weight gain and adipose tissue accumulation in female rats (Cooper et al, 2005; Han et al, 2008; Weston-Green et al, 2011). The other limitation is that, besides the liver, cevimeline may also act on other tissues or organs expressed muscarinic M3 receptors (Arisawa et al, 2002b; Kim et al, 2021). It has been well documented that olanzapine can modulate insulin release by directly acting on the pancreatic beta cells (Chen et al, 2017; Johnson et al, 2005; Silvestre and Prous, 2005; Weston-Green et al, 2013).…”

Membrane Trafficking of Integral Cell Junction Proteins

“…The endocytosed claudin-2 traversed early endosomes and collocated with LAMP1, but not with the Golgi apparatus, suggesting it was targeted for lysosomal degradation rather than recycling. Cevimeline, a specific agonist of the M1 and M3 muscarinic acetylcholine (Ach) receptors [9], as well as carbachol, a non-selective Ach receptor agonist analog, induced claudin-4 binding to clathrin and to the endocytic sorting protein arrestin-β2 in immortalized rat salivary gland epithelial cells [39]. This effect was specific to claudin, as the interaction of occludin and epithelial (E)-cadherin with arrestin-β2 were not altered by carbachol.…”

“…The clathrin dependence of claudin-4 endocytosis was established by showing that it was blocked by pharmacological inhibition of dynamin [135] by siRNA-mediated knockdown of the clathrin heavy chain, and by hypertonic sucrose medium. [53], (4) [62], (5) [71], (6) [94], (7) [95], (8) [96], (9) [100], (10) [127], (11) [128], (12) [132], (13) [137], (14) [139], (15) [141], (16) [158], (17) [168], (18) [192], (19) [203], (20) [217], (21) [219], (22) [227], (23) [231], (24) [242], (25) [243], (26) [258], (27) [264].…”

“…EE, early endosome; LE, late endosome; Lys, lysosome; RE, recycling endosome. Numbers correspond to the following references: (1) [39], (2) ([52], (3) [53], (4) [62], (5) [71], (6)[94],(7) [95],(8) [96],(9) [100], (10)[127],(11) [128], (12)[132],(13) [137],(14) [139],(15) [141],(16) [158],(17) [168],(18) [192],(19) [203],(20) [217],(21) [219],(22) [227],(23) [231],(24) [242],(25) [243],(26) [258],(27) [264].…”