ω-Conotoxin GVIA mimetics based on an anthranilamide core: Effect of variation in ammonium side chain lengths and incorporation of fluorine

ω-Conotoxin GVIA Mimetics that Bind and Inhibit Neuronal Cav2.2 Ion Channels

“…The previously described synthetic route to the anthranilamide-based mimics [32] was modified to allow incorporation of the diphenylmethylpiperazine moiety at a later stage in the synthesis, thus facilitating the preparation of a small library of compounds from a common, advanced precursor. This advanced precursor was the diazide ( 5 ), which was prepared in four steps from the previously reported nitro ester ( 1 ) [32], as shown in Scheme 1.…”

“…Subsequently, Lewis’ group developed a cyclic pentapeptide that mimics the action of ω-conotoxin CVID [28]. We have been investigating non-peptidic mimics of ω-conotoxin GVIA based on benzothiazole [29,30] and anthranilamide [31,32] cores. These mimics, which bear tyrosine, lysine and arginine side chain mimics projected from a central scaffold were designed based on Bartlett and Lauri’s Cα-Cβ bond vector philosophy, but—crucially—not involving automated scaffold retrieval but rather interactive de novo design [23,24,33].…”

“…An investigation of the mimic based on the anthranilamide scaffold involved variation of the length of the side chains, the incorporation of two guanidino moieties, and two variations of the diphenyl ether substituent (see Figure 1) [32]. Key findings from this study were that; (a) typically diguanidino compounds [Z = N=(NH 2 ) 2 ] had binding activity in the 6–16 μM range in a radio-labelled ω-conotoxin GVIA displacement assay, whereas diamino compounds [Z = NH 2 ] bound more weakly and; (b) strongest affinity was found with a fluorinated mimic [X = F].…”

Conus Venom Peptide Pharmacology

“…266 increasingly clear, residues responsible for any splice variant selectivity of -conotoxins have not been determined to date. Nonetheless, our understanding of these structureactivity relationships are being applied to the design of small molecule, orally active -conotoxin peptidomimetics with the hope of engineering novel analgesic molecules based on the unique pharmacological properties of -conotoxins Andersson et al, 2009). …”

Strategies for the Development of Conotoxins as New Therapeutic Leads

“…The functionalized molecule bearing the Try13, Arg17 and Lys2 side chain mimics blocked Ca V 2.2 with micromolar affinity in a functional assay (68 μM) [41]. Further structure-activity relationship (SAR) studies surrounding the mimetic focused on the nature of the alkyl side chains and the use of both amino and guanidine groups [42,43]. Variation of the side chain lengths of both the Lys and Arg mimics did not generate any convincing SAR, although varying the terminal functionality on the Lys and Arg side chains did significantly affect activity.…”