(They) propose to characterize conantokin peptides for treatment of epilepsy. Conantokins, a family of small peptides (17-27 amino acids) isolated from the venom of fish-hunting cone snails, are specific antagonists of NMDA receptors in the mammalian central nervous system. Conantokins inhibit NMDA-elicited currents and NMDA- stimulated cyclic GMP formation. Their laboratories performed the first in vivo studies showing that conantokins exhibit a potent antiseizure activity in animals. Conantokins were shown to be some of the most potent compounds ever tested in the Frings audiogenic seizure-susceptible mouse model. In addition, conantokins showed low neurotoxicity, as determined by relating the toxic dose (rotorod performance) to the effective dose. Therefore, conantokins represent a unique, highly potent and novel class of compounds for treatment of CNS disorders. In Phase I, we propose to: test conantokins for antiseizure activity using three different experimental animal models; compare the in vivo antiseizure activity of conantokins with their in vitro receptor binding activity; identify and evaluate new natural conantokins; and synthesize chimeras of conantokins to initiate structure function studies. In Phase II, more extensive in vivo characterization of conantokins for treatment of seizure disorders will be carried out. Moreover, they will establish a program for synthesis of conantokin peptidomimetics, which should increase the bioavailability of these molecules.
