Xanomeline oxalate

Xanomeline oxalate is a novel agonist of muscarinic receptor with the pKi values of 7.1±0.1, 6.9±0.1, 7.4±0.1, 7.7±0.1 and 7.4±0.2 for hM1, hM2, hM3, hM4 and hM5, respectively. [1].

Xanomeline oxalate has been reported to have the highest affinity for [3H]oxotremorine-M cortical and [3H]pirenzepine hippocampal labeled muscarinic receptors（2±0.5nM and 5±1nM, respectively）. In addition, Xanomeline oxalate has been revealed to produce a concentration-dependent inhibition of electrically stimulated twitch response in isolated rabbit vas deferens with the IC50 value of 0.006nM. Furthermore, Xanomeline oxalate has also been noted to produce the carbachol-stimulated PI hydrolysis with the IC50 values of 0.004±0.001μM, 21±4μM and 0.2±0.08μM in CHO-K1 cell, BHK cell and A9L cell, respectively. Besides, Xanomeline oxalate has been reported to reduce the force of contraction of guinea pig isolated atria with an IC50 value of ~3μM and produce a concentration-dependent contractile response in the guinea pig ileum with an IC50 value of 9nM [2].

References:
[1]Watson J1, Brough S, Coldwell MC, Gager T, Ho M, Hunter AJ, Jerman J, Middlemiss DN, Riley GJ, Brown AM. Functional effects of the muscarinic receptor agonist, xanomeline, at 5-HT1 and 5-HT2 receptors. Br J Pharmacol. 1998 Dec;125(7):1413-20.
[2]Shannon HE1, Bymaster FP, Calligaro DO, Greenwood B, Mitch CH, Sawyer BD, Ward JS, Wong DT, Olesen PH, Sheardown MJ, et al. Xanomeline: a novel muscarinic receptor agonist with functional selectivity for M1 receptors. J Pharmacol Exp Ther. 1994 Apr;269(1):271-81.

3-[3-(3-florophenyl-2-propyn-1-ylthio)-1, 2, 5-thiadiazol-4-yl]-1, 2, 5, 6-tetrahydro-1- methylpyridine oxalate, a novel xanomeline derivative, improves neural cells proliferation and survival in adult mice.[Pubmed:25806054]

Neural Regen Res. 2012 Jan 5;7(1):24-30.

The present study analyzed the influence of 3-[3-(3-florophenyl-2-propyn-1-ylthio)-1, 2, 5-thiadiazol-4-yl]-1, 2, 5, 6-tetrahydro-1-methylpyridine oxalate (EUK1001), a novel xanomeline derivative of the M1/M4 receptor agonist, on hippocampal neurogenesis in adult C57BL6 mice. Results showed that 15-day EUK1001 treatment via intraperitoneal injection promoted neural cell proliferation in the dentate gyrus, although cell differentiation did not change. The majority of bromodeoxyuridine-positive cells co-expressed the immature neuronal marker doublecortin. In addition, the level of neurogenesis in the subventricular zone was not altered. Brain-derived neurotrophic factor mRNA expression was up-regulated following EUK1001 treatment, but no change was observed in expression of camp-responsive element binding protein 1, paired box gene 6, vascular endothelial growth factor alpha, neurogenic differentiation factor 1, and wingless-related mouse mammary tumor virus integration site 3A mRNA. These experimental findings indicated that EUK1001 enhanced proliferation and survival of hippocampal cells, possibly by increasing brain-derived neurotrophic factor expression.

Pharmacological comparison of muscarinic ligands: historical versus more recent muscarinic M1-preferring receptor agonists.[Pubmed:19168056]

Eur J Pharmacol. 2009 Mar 1;605(1-3):53-6.

In functional assay assessments using the five muscarinic receptor subtypes, a second generation of muscarinic M(1)-preferring receptor agonists [AC-42 (1), AC-260584 (2), 77-LH-28-1 (3) and LY-593039 (4)] was shown to have higher selectivity for muscarinic M(1) over M(3) receptor as compared to historical agonists [talsaclidine (8), sabcomeline (10), xanomeline (11), WAY-132983 (12), cevimeline (9) and NGX-267 (6)]. Another striking difference of these more recent compounds is their affinities for the dopamine D(2) and 5-HT(2B) receptors. Taken together, these results suggest that the newer compounds may have a greater clinical safety profile, especially with regard to muscarinic M(3) receptor-mediated events, than the historical agonists, but their affinities for other receptors may still compromise their use to validate the therapeutic potential of muscarinic M(1) receptor agonists.

Importance and prospects for design of selective muscarinic agonists.[Pubmed:18481916]

Physiol Res. 2008;57 Suppl 3:S39-47. Epub 2008 May 13.

There are five subtypes of muscarinic receptors that serve various important physiological functions in the central nervous system and the periphery. Mental functions like attention, learning, and memory are attributed to the muscarinic M1 subtype. These functions decline during natural aging and an early deficit is typical for Alzheimer s disease. In addition, stimulation of the M1 receptor increases non-amyloidogenic processing of the amyloid precursor protein and thus prevents accumulation of noxious beta-amyloid fragments. The selectivity of classical muscarinic agonists among receptor subtypes is very low due to the highly conserved nature of the orthosteric binding site among receptor subtypes. Herein we summarize some recent studies with the functionally-selective M1 agonist xanomeline that indicate complex pharmacological profile of this drug that includes interactions with and activation of receptor from both orthosteric and ectopic binding sites, and the time-dependent changes of ligand binding and receptor activation. These findings point to potential profitability of exploitation of ectopic ligands in the search for truly selective muscarinic receptor agonists.