Halogen substituents on the aromatic moiety of the tetracaine scaffold improve potency of cyclic nucleotide-gated channel block

A series of new tetracaine derivatives with substituents on the aromatic ring was prepared and evaluated for block of retinal rod cyclic nucleotide-gated (CNG) channels. Aromatic substitutions had little effect starting with the basic tetracaine scaffold, but electron-withdrawing substituents signif...

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Bibliographic Details
Published in:Bioorganic & medicinal chemistry letters 2011-11, Vol.21 (21), p.6417-6419
Main Authors: Kirk, Sarah R., Andrade, Adriana L., Melich, Kenneth, Jackson, Evan P., Cuellar, Elysia, Karpen, Jeffrey W.
Format: Article
Language:English
Subjects:
aminobenzoic acids
antagonists
Aromatics
Biological and medical sciences
cGMP
chemical derivatives
Cyclic Nucleotide-Gated Cation Channels - antagonists & inhibitors
Eye
Halogens
Halogens - chemistry
Ion channels
ion channels (cyclic nucleotide-gated)
Local anesthetics
Medical sciences
Pharmacology. Drug treatments
Pore blockers
Retina
Retinal rods
rods (retina)
scaffolds
structure-activity relationships
tetracaine
Tetracaine - chemistry
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Summary:A series of new tetracaine derivatives with substituents on the aromatic ring was prepared and evaluated for block of retinal rod cyclic nucleotide-gated (CNG) channels. Aromatic substitutions had little effect starting with the basic tetracaine scaffold, but electron-withdrawing substituents significantly improved the blocking potency of an octyl-tail derivative of tetracaine. In particular, halogen substitutions at either the 2- or 3-position on the ring resulted in compounds that were up to eight-fold more potent than the parent octyl-tail derivative and up to 50-fold more potent than tetracaine.
ISSN:0960-894X
1464-3405
DOI:10.1016/j.bmcl.2011.08.092