✍ Scribed by Kristian Strømgaard; Ian Mellor
No coin nor oath required. For personal study only.
α‐Amino‐3‐hydroxy‐5‐methyl‐4‐isoxazole propionic acid (AMPA) receptors (AMPAR), subtype of the ionotropic glutamate receptors (IGRs), mediate fast synaptic transmission in the central nervous system (CNS), and are involved in many neurological disorders, as well as being a key player in the formation of memory. Hence, ligands affecting AMPARs are highly important for the study of the structure and function of this receptor, and in this regard polyamine‐based ligands, particularly polyamine toxins, are unique as they selectively block Ca^2+^‐permeable AMPARs. Indeed, endogenous intracellular polyamines are known to modulate the function of these receptors in vivo. In this study, recent developments in the medicinal chemistry of polyamine‐based ligands are given, particularly focusing on the use of solid‐phase synthesis (SPS) as a tool for the facile generation of libraries of polyamine toxin analogues. Moreover, the recent development of highly potent and very selective AMPAR ligands is described. Additionally, we provide a detailed account on the mechanism and site of action of AMPAR blockade by polyamine‐based ligands, including examples of how these ligands are used as tools to study AMPAR, and a comparison with their action on other ionotropic receptors. © 2004 Wiley Periodicals, Inc. Med Res Rev, 24, No. 5, 589–620, 2004
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## Abstract Polyamine toxins, such as philanthotoxins, are low‐molecular‐weight compounds isolated from spiders and wasps, which modulate ligand‐gated ion channels in the nervous system. Philanthotoxins bind to the pore‐forming region of AMPA receptors, a subtype of glutamate receptors which are im