Stromgaard K, Brierley M J, Andersen K, Sløk F A, Mellor I R, Usherwood P N, Krogsgaard-Larsen P, Jaroszewski J W
Department of Medicinal Chemistry and NeuroScience PharmaBiotec Research Center, Royal Danish School of Pharmacy, Universitetsparken 2, DK-2100 Copenhagen, Denmark.
J Med Chem. 1999 Dec 16;42(25):5224-34. doi: 10.1021/jm9903747.
Philanthotoxin-433 (PhTX-433), a natural polyamine wasp toxin, is a noncompetitive antagonist of certain ionotropic receptors. Six analogues of PhTX-343 (a synthetic analogue of the natural product), in which the secondary amino groups are systematically replaced by oxygen or methylene groups, have been synthesized by coupling of N-(1-oxobutyl)tyrosine with 1,12-dodecanediamine, 4,9-dioxa-1, 12-dodecanediamine, or appropriately protected di- and triamines, the latter being obtained by multistep syntheses. The resulting PhTX-343 analogues were purified and characterized, and their protolytic properties (stepwise macroscopic pK(a) values) were determined by (13)C NMR titrations. All analogues are fully protonated at physiological pH. The effects of these compounds on acetylcholine-induced currents in TE671 cells clamped at various holding potentials were determined. All of the analogues noncompetitively antagonized the nicotinic acetylcholine receptor (nAChR) in a concentration-, time-, and voltage-dependent manner. The amplitudes of acetylcholine-induced currents were compared at their peaks and at the end of a 1 s application in the presence or absence of the analogues. Most of the analogues were equipotent with or more potent than PhTX-343. The dideaza analogue PhTX-12 [IC(50) of 0.3 microM (final current value)] was the most potent, representing the highest potency improvement (about 50-fold) yet achieved by modification of the parent compound (PhTX-343). Thus, the presence of multiple positive charges in the PhTX-343 molecule is not necessary for antagonism of nAChR. In contrast, the compounds were much less potent than PhTX-343 at locust muscle ionotropic glutamate receptors sensitive to quisqualate (qGluR). The results demonstrate that the selectivity for different types of ionotropic receptors can be achieved by manipulating the polyamine moiety of PhTX-343.
philanthotoxin - 433（PhTX - 433）是一种天然多胺黄蜂毒素，是某些离子型受体的非竞争性拮抗剂。通过将N -（1 - 氧代丁基）酪氨酸与1,12 - 十二烷二胺、4,9 - 二氧杂 - 1,12 - 十二烷二胺或适当保护的二胺和三胺偶联，合成了六种PhTX - 343（天然产物的合成类似物）类似物，后者通过多步合成获得。对所得的PhTX - 343类似物进行了纯化和表征，并通过¹³C NMR滴定法测定了它们的质子解离性质（逐步宏观pK(a)值）。所有类似物在生理pH下均完全质子化。测定了这些化合物对在不同钳制电位下的TE671细胞中乙酰胆碱诱导电流的影响。所有类似物均以浓度、时间和电压依赖性方式非竞争性拮抗烟碱型乙酰胆碱受体（nAChR）。在存在或不存在类似物的情况下，比较了乙酰胆碱诱导电流在其峰值和施加1 s结束时的幅度。大多数类似物与PhTX - 343等效或比其更有效。双脱氮类似物PhTX - 12 [IC(50)为0.3 microM（最终电流值）]是最有效的，代表了通过修饰母体化合物（PhTX - 343）迄今实现的最高效价提高（约50倍）。因此，PhTX - 343分子中存在多个正电荷对于拮抗nAChR并非必要。相反，这些化合物在对喹啉酸敏感的蝗虫肌肉离子型谷氨酸受体（qGluR）上的效价比PhTX - 343低得多。结果表明，通过操纵PhTX - 343的多胺部分可以实现对不同类型离子型受体的选择性。
