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 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.
Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University , 381 Royal Parade, Parkville 3052, Victoria Australia.
Sandeep
S
Chhabra
Alessia
A
Belgi
Peter
P
Bartels
Bianca J
BJ
van Lierop
Samuel D
SD
Robinson
Shiva N
SN
Kompella
Andrew
A
Hung
Brid P
BP
Callaghan
David J
DJ
Adams
Andrea J
AJ
Robinson
Raymond S
RS
Norton
D000595:Amino Acid Sequence; D000700:Analgesics; D000818:Animals; D020864:Calcium Channels, N-Type / Q000187:drug effects; D020916:Conotoxins / Q000737:chemistry / Q000494:pharmacology*; D057809:HEK293 Cells; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D056004:Molecular Dynamics Simulation; D051381:Rats; D011978:Receptors, Nicotinic / Q000187:drug effects*
D000700:Analgesics; D020864:Calcium Channels, N-Type; D020916:Conotoxins; D011978:Receptors, Nicotinic; C510079:conotoxin alpha-RgIA, Conus regius