1 research outputs found
Dicarba Analogues of α‑Conotoxin RgIA. Structure, Stability, and Activity at Potential Pain Targets
α-Conotoxin
RgIA is both an antagonist of the α9α10
nicotinic acetylcholine receptor (nAChR) subtype and an inhibitor
of high-voltage-activated N-type calcium channel currents. RgIA has
therapeutic potential for the treatment of pain, but reduction of
the disulfide bond framework under physiological conditions represents
a potential liability for clinical applications. We synthesized four
RgIA analogues that replaced native disulfide pairs with nonreducible
dicarba bridges. Solution structures were determined by NMR, activity
assessed against biological targets, and stability evaluated in human
serum. [3,12]-Dicarba analogues retained inhibition of ACh-evoked
currents at α9α10 nAChRs but not N-type calcium channel
currents, whereas [2,8]-dicarba analogues displayed the opposite pattern
of selectivity. The [2,8]-dicarba RgIA analogues were effective in
HEK293 cells stably expressing human Ca<sub>v</sub>2.2 channels and
transfected with human GABA<sub>B</sub> receptors. The analogues also
exhibited improved serum stability over the native peptide. These
selectively acting dicarba analogues may represent mechanistic probes
to explore analgesia-related biological receptors