Conantokin G (Con G) toxin found in the venom of cone snails is a 17-amino-acid competitive antagonist of N-methyl-D-aspartate (NMDA) receptors containing NR2B subunits1. 



Conantokins were first discovered and isolated from the venom of cone snail, Conus geographus as it induced a sleep-like state in mice2.



Conantokins belong to a unique family of ?-carboxyglutamic acid-containing Conus peptides.  There are three members of conantokins that have been identified so far- Conantokins G, T and R3.


Structural Characteristics

Con G has the sequence- H - Gly - Glu - Gla - Gla - Leu - Gln - Gla - Asn - Gln - Gla - Leu - Ile - Arg - Gla - Lys - Ser - Asn - NH21.  It is a linear peptide that possesses a high degree of alpha-helicity in the presence of divalent cations, and contains gamma-carboxyglutamic acid residues1.


Mode of action

Con G undergoes several post translational processing one of which is the vitamin K-dependent gamma-carboxylation of glutamate that results in placement of gamma-carboxyglutamic acid residues in these peptides4. As a result, these peptides then possess the ability to interact with divalent metal ions and concomitantly undergo a conformational alteration4.  They then interact with the glutamate binding pocket of NMDA receptors and inhibit them5.



The pharmacological selectivity of the Con G, coupled with its efficacy in preclinical models of disease indicate that it can be used as a probe for NMDA receptor function as well as for continued investigation as human therapeutics1.





1.     Layer RT, Wagstaff JD, White HS (2004). Conantokins: peptide antagonists of NMDA receptors. Curr Med Chem, 1(23):3073-84.

2.     McIntosh JM, Olivera BM, Cruz LJ, Gray WR (1984). Gamma-carboxyglutamate in a neuroactive toxin. J Biol Chem, 10; 259(23):14343-6.

3.     Prorok M, Castellino FJ (2001). Structure-function relationships of the NMDA receptor antagonist conantokin peptides. Curr Drug Targets, 2(3):313-22.

4.     Castellino FJ, Prorok M (2000). Conantokins: inhibitors of ion flow through the N-methyl-D-aspartate receptor channels. Curr Drug Targets, 1(3):219-35.

5.     Wittekindt B, Malany S, Schemm R, Otvos L, Maccecchini ML, Laube B and Betz H (2006). Point mutations identify the glutamate binding pocket of the N-methyl- -aspartate receptor as major site of Conantokin-G inhibition. Neuropharmacology
41 (6), 753-761.

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