title: Cyclic nucleotide-gated channel block by hydrolysis-resistant tetracaine derivatives.
abstract: To meet a pressing need for better cyclic nucleotide-gated (CNG) channel antagonists, we have increased the biological stability of tetracaine-based blockers by synthesizing amide and thioamide linkage substitutions of tetracaine (1) and a higher affinity octyl tail derivative (5). We report the apparent K(D) values, the mechanism of block, and the in vitro hydrolysis rates for these compounds. The ester linkage substitutions did not adversely affect CNG channel block; unexpectedly, thioamide substitution in 1 (compound 8) improved block significantly. Furthermore, the ester linkage substitutions did not appear to affect the mechanism of block in terms of the strong state preference for closed channels. All ester substituted compounds, especially the thioamide substitutions, were more resistant to hydrolysis by serum cholinesterase than their ester counterparts. These findings have implications for dissecting the physiological roles of CNG channels, treating certain forms of retinal degeneration, and possibly the current clinical uses of compound 1.
authors.affiliation: Department of Physiology and Pharmacology, Oregon Health & Science University, Portland, Oregon 97239, United States.
authors.forename: Adriana L
authors.initials: AL
authors.lastname: Andrade
authors.forename: Kenneth
authors.initials: K
authors.lastname: Melich
authors.forename: G Gregory
authors.initials: GG
authors.lastname: Whatley
authors.forename: Sarah R
authors.initials: SR
authors.lastname: Kirk
authors.forename: Jeffrey W
authors.initials: JW
authors.lastname: Karpen
mesh_terms: D000818:Animals; D002091:Butyrylcholinesterase / Q000737:chemistry; D006152:Cyclic GMP / Q000378:metabolism; D054815:Cyclic Nucleotide-Gated Cation Channels / Q000037:antagonists & inhibitors* / Q000737:chemistry; D005260:Female; D006801:Humans; D006868:Hydrolysis; D066298:In Vitro Techniques; D009865:Oocytes / Q000187:drug effects / Q000502:physiology; D018408:Patch-Clamp Techniques; D017948:Retinal Rod Photoreceptor Cells / Q000378:metabolism; D013329:Structure-Activity Relationship; D013748:Tetracaine / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000494:pharmacology; D014981:Xenopus
chemical_list: D054815:Cyclic Nucleotide-Gated Cation Channels; D013748:Tetracaine; D002091:Butyrylcholinesterase; D006152:Cyclic GMP