title: Synthesis and biological evaluation of nonpeptide mimetics of omega-conotoxin GVIA.
abstract: A benzothiazole-derived compound (4a) designed to mimic the C(alpha)-C(beta) bond vectors and terminal functionalities of Lys2, Tyr13 and Arg17 in omega-conotoxin GVIA was synthesised, together with analogues (4b-d), which had each side-chain mimic systematically truncated or eliminated. The affinity of these compounds for rat brain N-type and P/Q-type voltage gated calcium channels (VGCCs) was determined. In terms of N-type channel affinity and selectivity, two of these compounds (4a and 4d) were found to be highly promising, first generation mimetics of omega-conotoxin. The fully functionalised mimetic (4a) showed low microM binding affinity to N-type VGCCs (IC(50)=1.9 microM) and greater than 20-fold selectivity for this channel sub-type over P/Q-type VGCCs, whereas the mimetic in which the guanidine-type side chain was truncated back to an amine (4d, IC(50)= 4.1 microM) showed a greater than 25-fold selectivity for the N-type channel.
authors.affiliation: Biomolecular Research Institute, 343 Royal Parade, Parkville, Victoria 3052, Australia. jbaell@wehi.edu.au
authors.forename: Jonathan B
authors.initials: JB
authors.lastname: Baell
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Duggan
authors.forename: Stewart A
authors.initials: SA
authors.lastname: Forsyth
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Lewis
authors.forename: Y Phei
authors.initials: YP
authors.lastname: Lok
authors.forename: Christina I
authors.initials: CI
authors.lastname: Schroeder
mesh_terms: D000818:Animals; D001667:Binding, Competitive / Q000187:drug effects; D001923:Brain Chemistry; D002121:Calcium Channel Blockers / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D020864:Calcium Channels, N-Type / Q000187:drug effects*; D020865:Calcium Channels, P-Type / Q000187:drug effects; D020907:Calcium Channels, Q-Type / Q000187:drug effects; D015195:Drug Design; D008958:Models, Molecular; D018716:Molecular Mimicry; D015394:Molecular Structure; D011869:Radioligand Assay; D051381:Rats; D013329:Structure-Activity Relationship; D020866:omega-Conotoxin GVIA / Q000737:chemistry* / Q000494:pharmacology
chemical_list: D002121:Calcium Channel Blockers; D020864:Calcium Channels, N-Type; D020865:Calcium Channels, P-Type; D020907:Calcium Channels, Q-Type; D020866:omega-Conotoxin GVIA