young mice, with faster onset and for a longer duration. Con-L blocks NMDA-evoked currents in a powerful way, which is only slowly reversible upon washout, similar to Con-R and Con-G. Conantokin-Pr1, -Pr2 and –Pr3 Each peptide in this group is derived from the same species, Conus parius. Con-Pr3 () has three different post-translational modifications. Con-Pr1 () and –Pr2 () adopt α-helical conformations in the presence of Mg2+ and Ca2+, but otherwise are generally unstructured. Conantokin-Pr3 always adopts an α-helical conformation. These peptides have highest potency for the NR2B subunits of the NMDAR. Conantokin-P and -E Con-P () and Con-E () were isolated from the only two fish-hunting cone snails of the Americas (Conus purpurascens and Conus ermineus, respectively). Con-P differs from the other known conantokins in that it contains a long disulfide loop with two Gla residues. It is less helical (estimated 44% helical content), but unlike con-G, it does not require calcium for stability of this structure. Another notable distinction is the increased discrimination for NR2B. Con-E is very similar in structure to Con-P, and is likely to have a similar function. Conantokin-Rl-A Con-Rl-A (), derived from the venom of Conus rolani, is unique among the conantokins in having two distinct conformational states between which it equilibriates. Like Con-P and Con-E, its helical structure (estimated at 50%) does not depend on the presence or absence of calcium. This is likely due to the fact that two of the five Gla residues present in con-G are replaced in con-Rl-A by Lys. Con-R1-A discriminates more effectively than any other known ligand between the NR2B and NR2C subunits of NMDAR. Conantokin-Br or -S1 Con-Br (or Con-S1, ) is isolated from Conus brettinghami (now Conus sulcatus), and is the only known conantokin with a high selectivity for the NR2D subunit of NMDAR. Synthetic derivatives Con-G-based Con-G[γ7A] Con-G[γ7K] and Con-G[S16Y] are synthetic Con-G peptides, where the Gla residue at position 7 is replaced with an alanine or a lysine residue, or the serine at position 16 is replaced with a tyrosine residue, respectively. Con-G[γ7A] is fourfold more potent than the native peptide, Con-G, while Con-G[γ7K] is as potent as Con-G. The first two peptides appear to distinguish NMDAR subtypes in mid-frontal gyri from those in superior temporal gyri in human brain tissue. Both of them are being researched in relation to Alzheimer’s disease (AD) and all three evoked 100% inhibition of spermine-enhanced [3H]MK-801 binding.