Guaifenesin Derivatives Promote Neurite Outgrowth and Protect Diabetic Mice from Neuropathy

Abstract

In diabetic patients, an early index of peripheral neuropathy is the slowing of conduction velocity in large myelinated neurons and a lack of understanding of the basic pathogenic mechanisms hindered therapeutics development. Racemic (R/S)-guaifenesin (1) was identified as a potent enhancer of neurite outgrowth using an in vitro screen. Its R-enantiomer (R)-1 carried the most biological activity, whereas the S-enantiomer (S)-1 was inactive. Focused structural variations to (R/S)-1 was conducted to identify potentially essential groups for the neurite outgrowth activity. In vivo therapeutic studies indicated that both (R/S)-1 and (R)-1 partially prevented motor nerve conduction velocity slowing in a mouse model of type 1 diabetes. In vitro microsomal assays suggested that compounds (R)-1 and (S)-1 are not metabolized rapidly, and PAMPA assay indicated moderate permeability through the membrane. Findings revealed here could lead to the development of novel drugs for diabetic neuropathy.

Selective antagonism of muscarinic receptors is neuroprotective in peripheral neuropathy

“…The broad-spectrum nicotinic antagonists hexaarticle; doi:10.1172/JCI88321DS1; and previously described in ref. 28) identified pirenzepine, a selective M 1 R antagonist (29), as able to induce a dose-dependent (3 to 100 nM) increase of total neurite outgrowth from neurons derived from normal rats ( Figure 1, A and B). This effect was mimicked by 30 nM VU0255035, a structurally dissimilar but also selective M 1 R antagonist (30) (Figure 1C).…”

A Network Pharmacology Approach to Determine Active Compounds and Action Mechanisms of Ge‐Gen‐Qin‐Lian Decoction for Treatment of Type 2 Diabetes

“…These ingredients were linked to diverse antidiabetic activities in previous studies and were computationally confirmed here. For example, 1-OCTEN-3-OL from Ge-Gen and 2-Acetyl-1-methylpyrrole from Gan-Cao were found to be antioxidants involved in the improvement of diabetes [50, 63, 64]; guaifenesin from Huang-Qin promoted neurite outgrowth and protected diabetic mice from neuropathy [61]. In particular, several core ingredients from Huang-Lian, berberine bisulfate, columbamine, coptisine, epiberberine, jatrorrhizine, oxyberberine, dehydrocheilanthifoline, and berberine were reported to have hypoglycemic and antidiabetic actions through the regulation of glucose metabolic effects and reduction of oxidative stress injury [51–59].…”

Stereoselective Crystallization as a Basis for Single‐Enantiomer Drug Production

“…Back in 2003, during a study of a series of TAGEs, we found that the registered drug guaifenesin 38 has the property of spontaneous resolution . Guaifenesin is usually classified as the centrally acting muscle relaxant with expectorant properties e, but there is evidence that it has other types of activity . In this last paper, the various activities of individual enantiomers have also been demonstrated.…”