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They share a high degree of structural resemblance, their aromatic head groups being the only difference, and were recently found to be very potent open\u2010channel blockers of ionotropic glutamate (iGlu) receptors. In this study we designed and synthesized a collection of 24 analogues of these toxins using a recently developed solid\u2010phase synthetic methodology. Systematic variation in two regions of the toxins and subsequent evaluation of biological activity at AMPA and NMDA subtypes of iGlu receptors provided succinct information on structure\u2013activity relationships. In particular, one set of analogues were found to display exquisite selectivity and potency for AMPA receptors relative to the natural products. Thus, this systematic SAR study has provided new pharmacological tools for studies of iGlu receptors.<\/jats:p>","DOI":"10.1002\/cmdc.201402278","type":"journal-article","created":{"date-parts":[[2014,10,6]],"date-time":"2014-10-06T11:47:47Z","timestamp":1412596067000},"page":"2661-2670","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Structure\u2013Activity Relationship Study of Spider Polyamine Toxins as Inhibitors of Ionotropic Glutamate Receptors"],"prefix":"10.1002","volume":"9","author":[{"given":"Xiao\u2010Feng","family":"Xiong","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mette H.","family":"Poulsen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rama A.","family":"Hussein","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Niels G.","family":"N\u00f8rager","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kristian","family":"Str\u00f8mgaard","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2014,9,29]]},"reference":[{"key":"e_1_2_6_1_2","doi-asserted-by":"publisher","DOI":"10.1124\/pr.109.002451"},{"key":"e_1_2_6_2_2","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-physiol-030212-183711"},{"key":"e_1_2_6_3_2","unstructured":"\u00a0"},{"key":"e_1_2_6_4_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.tips.2011.08.003"},{"key":"e_1_2_6_5_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrn3504"},{"key":"e_1_2_6_6_2","unstructured":"\u00a0"},{"key":"e_1_2_6_7_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrd1958"},{"key":"e_1_2_6_8_2","doi-asserted-by":"publisher","DOI":"10.2165\/11201020-000000000-00000"},{"key":"e_1_2_6_9_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1476-5381.2012.02057.x"},{"key":"e_1_2_6_10_2","unstructured":"\u00a0"},{"key":"e_1_2_6_11_2","doi-asserted-by":"publisher","DOI":"10.1517\/14656566.2010.515978"},{"key":"e_1_2_6_12_2","doi-asserted-by":"publisher","DOI":"10.1111\/cns.12111"},{"key":"e_1_2_6_13_2","doi-asserted-by":"publisher","DOI":"10.5055\/jom.2013.0180"},{"key":"e_1_2_6_14_2","unstructured":"\u00a0"},{"key":"e_1_2_6_15_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrd2462"},{"key":"e_1_2_6_16_2","doi-asserted-by":"publisher","DOI":"10.1176\/appi.ajp.2012.12040531"},{"key":"e_1_2_6_17_2","doi-asserted-by":"publisher","DOI":"10.2174\/13816128113199990293"},{"key":"e_1_2_6_18_2","unstructured":"\u00a0"},{"key":"e_1_2_6_19_2","doi-asserted-by":"publisher","DOI":"10.1002\/med.20004"},{"key":"e_1_2_6_20_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.toxicon.2004.02.003"},{"key":"e_1_2_6_21_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.toxicon.2004.11.013"},{"key":"e_1_2_6_22_2","doi-asserted-by":"publisher","DOI":"10.1002\/anie.201101599"},{"key":"e_1_2_6_22_3","doi-asserted-by":"publisher","DOI":"10.1002\/ange.201101599"},{"key":"e_1_2_6_23_2","doi-asserted-by":"publisher","DOI":"10.1021\/jm5004705"},{"key":"e_1_2_6_24_2","unstructured":"\u00a0"},{"key":"e_1_2_6_25_2","doi-asserted-by":"publisher","DOI":"10.1016\/0896-6273(93)90061-U"},{"key":"e_1_2_6_26_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.90.14.6528"},{"key":"e_1_2_6_27_2","unstructured":"\u00a0"},{"key":"e_1_2_6_28_2","doi-asserted-by":"publisher","DOI":"10.1021\/jm020314s"},{"key":"e_1_2_6_29_2","doi-asserted-by":"publisher","DOI":"10.1002\/cmdc.200500093"},{"key":"e_1_2_6_30_2","doi-asserted-by":"publisher","DOI":"10.1021\/jm060606j"},{"key":"e_1_2_6_31_2","doi-asserted-by":"publisher","DOI":"10.1124\/mol.113.089961"},{"key":"e_1_2_6_32_2","unstructured":"\u00a0"},{"key":"e_1_2_6_33_2","first-page":"1121","volume":"12","author":"Grishin E. 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