Conantokins: Peptide Antagonists of NMDA Receptors

Abstract

Conantokins are small peptides (17-27 amino acids) found in the venoms of cone snails (Conus sp.) that inhibit the activity of N-methyl-D-aspartate (NMDA) receptors. Unlike most of the peptides characterized from cone snail venom that contain multiple disulfide bridges, conantokins are linear peptides that possess a high degree of alpha-helicity in the presence of divalent cations, and contain gamma-carboxyglutamic acid residues. Four naturally occurring conantokins have been identified and characterized to date, conantokin-G, conantokin-T, conantokin-R, and conantokin-L. The most extensively characterized, conantokin-G, is selective for subtypes of NMDA receptors containing the NR2B subunit. The conantokins have been synthesized and characterized in a number of animal models of human pathologies including pain, convulsive disorders, stroke, and Parkinson's disease. The potential pharmacological selectivity of the conantokins, coupled with their efficacy in preclinical models of disease and favorable safety profiles indicate that these peptides represent both novel probes for NMDA receptor function as well as an important class of compounds for continued investigation as human therapeutics.

Novel Conantokins from Conus parius Venom Are Specific Antagonists of N-Methyl-D-aspartate Receptors

“…This pharmacological selectivity has raised general interest in several potential clinical applications that include developing conantokin peptides as drugs for neuroprotection (e.g. after ischemic stroke) (9 -11), pain (12)(13)(14), epilepsy (3,6,7,15), and probing mechanisms of drug addiction (16). Con-G (CGX-1007, Cognetix, Inc.) has reached phase I clinical trials for both pain and epilepsy (14).…”

Conantokin G-induced changes in the chemical coding of dorsal root ganglion neurons supplying the porcine urinary bladder

“…It is also known that CTG inhibits NMDARs activation (Layer et al 2004) and exhibits potent antinociceptive properties by the reduction of neurotransmitter release from afferent nerve terminals (Marvizon et al 2002). Thus, it may be possible that, in pigs, intravesical injections of CTG can lead to an inhibition of SP release from bladder sensory nerve terminals, causing a reduction of inflammatory responses; however, this suggestion has to be confirmed in other studies.…”

Conotoxins: Possible Therapeutic Measure for Huntingtons Disease

“…Glutamate is the major excitatory transmitter in the brain. Glutamate information which regulates brain development and that determines cellular survival, differentiation and elimination as well as formation and elimination of nerve contacts (synapses) [17,20]. Glutamate interacts with at least three classes of membrane receptors, each commonly referred to by preferred pharmacological agonists: N-methyl-o-aspartate (NMDA), quisqualate, and kainate [21].…”

“…There is no proven effective therapy for Huntington's disease exists, It will be important to determine whether certain more effective treatments or have fewer side effects than others in disease states might be good approach to enhance the disease tolerance. NMDA receptor antagonist could be beneficial neuroprotective agents or ion channel blockers which inhibit glutamate-induced translocation of protein kinase C and thereby reducing exitotoxic neuronal cell death [4,20,27].…”