title: 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.
authors.affiliation: Department of Chemistry and Biochemistry, The University of North Carolina at Greensboro, Greensboro, North Carolina 27412, USA.
authors.forename: Mallinath B
authors.initials: MB
authors.lastname: Hadimani
authors.forename: Meena K
authors.initials: MK
authors.lastname: Purohit
authors.forename: Chandrashaker
authors.initials: C
authors.lastname: Vanampally
authors.forename: Randy
authors.initials: R
authors.lastname: Van der Ploeg
authors.forename: Victor
authors.initials: V
authors.lastname: Arballo
authors.forename: Dwane
authors.initials: D
authors.lastname: Morrow
authors.forename: Katie E
authors.initials: KE
authors.lastname: Frizzi
authors.forename: Nigel A
authors.initials: NA
authors.lastname: Calcutt
authors.forename: Paul
authors.initials: P
authors.lastname: Fernyhough
authors.forename: Lakshmi P
authors.initials: LP
authors.lastname: Kotra
mesh_terms: D000818:Animals; D003929:Diabetic Neuropathies / Q000473:pathology* / Q000517:prevention & control*; D005260:Female; D006140:Guaifenesin / Q000031:analogs & derivatives* / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology*; D006801:Humans; D008297:Male; D051379:Mice; D008862:Microsomes, Liver / Q000378:metabolism; D016501:Neurites / Q000187:drug effects* / Q000378:metabolism*; D010539:Permeability; D051381:Rats; D013237:Stereoisomerism
chemical_list: D006140:Guaifenesin