2mtu

Publication Abstract from PubMed

alpha-Conotoxin RgIA is an antagonist of the alpha9alpha10 nicotinic acetylcholine receptor (nAChR) subtype and also inhibits 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 non-reducible 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 alpha9alpha10 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 Cav2.2 channels and transfected with human GABAB 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.

Dicarba Analogues of alpha-Conotoxin RgIA. Structure, Stability and Activity at Potential Pain Targets.,Chhabra S, Belgi A, Bartels P, Vanlierop BJ, Robinson SD, Kompella SN, Hung A, Callaghan BP, Adams DJ, Robinson AJ, Norton RS J Med Chem. 2014 Nov 13. PMID:25393758^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.