Long-term potentiation in the presence of NMDA receptor antagonist arylalkylamine spider toxins

The role of the NMDA receptor (NMDAR) in long‐term potentiation (LTP) is now well established. All potent NMDAR antagonists known to date inhibit the induction of LTP at the Schaffer collateral‐CA1 pyramidal cell synapse in rat hippocampus, regardless of their site and mechanism of action. Arylalkylamine toxins are noncompetitive NMDAR antagonists in the mammalian central nervous system (CNS). The synthetic toxins argiotoxin‐636 (Arg‐636), Joro spider toxin (JSTX‐3), α‐agatoxin‐489 and ‐505 (Agel‐489 and Agel‐505) and philanthotoxin‐433 (δ‐PhTX) were found in the present study to have no effect on the induction of LTP in the Schaffer collateral‐CA1 pyramidal cell pathway in rat hippocampal slices maintained in vitro. Arylalkylamine toxins represent a class of potent NMDAR antagonists that fail to affect hippocampal LTP, and thus provide novel structural leads for the development of NMDAR antagonists that do not impair cognition. Excitatory amino acid (EAA) antagonists, especially those targeting the N‐methyl‐D‐aspartate receptor (NMDAR), have been the subject of intensive research over the past decade. It is anticipated that such agents will prove therapeutically useful in a wide variety of CNS disorders, including epilepsy, ischemic stroke, acute neural trauma, and neurodegenerative diseases such as Huntington's disease and Alzheimer's disease. A major drawback of all such compounds examined to date, be they competitive or noncompetitive antagonists, however, is their deleterious side effects such as impairment of cognition or psychotomimetic symptoms (Willetts et al., 1990). J. Neurosci. Res. 62:177–185, 2000. © 2000 Wiley‐Liss, Inc.