Dicarba α‑Conotoxin Vc1.1 Analogues with
Differential Selectivity for Nicotinic Acetylcholine and GABA<sub>B</sub> Receptors
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Abstract
Conotoxins
have emerged as useful leads for the development of
novel therapeutic analgesics. These peptides, isolated from marine
molluscs of the genus <i>Conus</i>, have evolved exquisite
selectivity for receptors and ion channels of excitable tissue. One
such peptide, α-conotoxin Vc1.1, is a 16-mer possessing an interlocked
disulfide framework. Despite its emergence as a potent analgesic lead,
the molecular target and mechanism of action of Vc1.1 have not been
elucidated to date. In this paper we describe the regioselective synthesis
of dicarba analogues of Vc1.1 using olefin metathesis. The ability
of these peptides to inhibit acetylcholine-evoked current at rat α9α10
and α3β4 nicotinic acetylcholine receptors (nAChR) expressed
in <i>Xenopus</i> oocytes has been assessed in addition
to their ability to inhibit high voltage-activated (HVA) calcium channel
current in isolated rat DRG neurons. Their solution structures were
determined by NMR spectroscopy. Significantly, we have found that
regioselective replacement of the native cystine framework with a
dicarba bridge can be used to selectively tune the cyclic peptide’s
innate biological activity for one receptor over another. The 2,8-dicarba
Vc1.1 isomer retains activity at γ-aminobutyric acid (GABA<sub>B</sub>) G protein-coupled receptors, whereas the isomeric 3,16-dicarba
Vc1.1 peptide retains activity at the α9α10 nAChR subtype.
These singularly acting analogues will enable the elucidation of the
biological target responsible for the peptide’s potent analgesic
activity