[a] IntroductionPhilanthotoxin-433 (PhTX-433, 1; the numerals indicate the number of methylene groups spacing the nitrogens in the polyamine moiety; Figure 1) is a toxin found naturally in the venom of the solitary wasp, Philanthus triangulum. [1,2] PhTX-433 and many of its synthetic analogues have been shown to have non-competitive inhibitory effects at both ionotropic glutamate receptors and nicotinic acetylcholine receptors. [3][4][5][6] In that respect PhTXs are attractive molecules to investigate further given that both of these receptor types are accepted as valid drug targets for a variety of neurodegenerative and other disorders of the central nervous system. [7] The modular butyryl-tyrosylthermospermine composition of 1 has allowed for efficient generation of many synthetic analogues demonstrating the importance of all of these structure segments. [4,6,[8][9][10][11] PhTXs 1, 2 and an array of other analogues have been shown to produce powerful voltage-dependent inhibition of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) currents suggesting a binding mode with the polyamine inserted deeply within the pore region of the ion channel.[3] This hypothesis is supported by the observation that AMPARs containing the GluA2 subunit with arginine at the "Q/R" site in the selectivity filter of the pore exhibit drastically reduced inhibition by PhTX-343 and other polyamine-containing molecules. [12] In the last two decades advanced methodologies for solidphase synthesis (SPS) of polyamines have been developed, [13] however, no examples of SPS of cyclopropane-containing polyamine derivatives have been reported. The commonly used solution-phase method for obtaining polyamines displaying a cyclopropane moiety is alkylation of mesitylenesulfonamides with mesitylenesulfonates of cyclopropane diols, but this is not readily transferred into an SPS protocol due to the harsh conditions required for deprotonation of the sulfonamide and the risk of cross-linking the resin due to the bifunctional building block. [14] Cyclopropane-trans-1,2-dicarboxylic acid [15] may be readily obtained from the corresponding ethyl diester and the cisanhydride 3-oxabicyclo[3.1.0]hexane-2,4-dione was commercially available, and therefore, we chose an approach involving on-resin reduction of the diamide corresponding to the desired 4,4'-dimethoxytrityl-protected polyamine. [16] In the present work we focus on incoporating unprecedented structural variations of the polyamine moiety present in both 1 and its well-studied close structural analogue, PhTX-343 (2), and examine how these influence the inhibitory effects of the resulting PhTX analogues on a specific subunit, GluA1flop, present in members of the AMPAR subdivision of the ionotropic glutamate receptor family. This subunit is characteristic of a calcium-permeable and polyamine-sensitive subtype of AMPARs, with the flop splice variant (a 38 amino acid region upstream of the fourth transmembrane region) being upregulated in place of the flip splice variant during early...