“…Similarly in NMDAR, Donevan and Rogawski found that antagonism by ArgTX-636 (18) could not be fully explained by open channel block and demonstrated that there was a component of competitive antagonism. 196 Polyamine-containing toxins also non-competitively antagonize quisqualate-sensitive glutamate receptors (qGluR) of invertebrates 167,[197][198][199] by closed-channel block as well as open channel block. 200,201 For example, ArgTX-636 (18) .…”
Section: Other Modes and Sites Of Action?mentioning
Alpha-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 Ca2+ -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.
“…Similarly in NMDAR, Donevan and Rogawski found that antagonism by ArgTX-636 (18) could not be fully explained by open channel block and demonstrated that there was a component of competitive antagonism. 196 Polyamine-containing toxins also non-competitively antagonize quisqualate-sensitive glutamate receptors (qGluR) of invertebrates 167,[197][198][199] by closed-channel block as well as open channel block. 200,201 For example, ArgTX-636 (18) .…”
Section: Other Modes and Sites Of Action?mentioning
Alpha-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 Ca2+ -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.
“…PhTX-433 is the main venom constituent responsible for paralyzing the arthropod prey of this wasp through its antagonism of ionotropic glutamate receptors (GluR) present on skeletal muscle. − The synthetic analogue PhTX-343 ( 2 ) of the natural product also antagonizes these receptors . Subsequently, a large number of analogues have been synthesized − and demonstrated to have a varying degree of noncompetitive antagonistic effect on insect muscle GluR, ,,,, insect and the Torpedo nicotinic acetylcholine receptors (nAChR), ,,, and on native and cloned mammalian brain GluR. ,− The interest in philanthotoxins is primarily due to their potential as therapeutic agents, for example for neuroprotection, and their importance as probes for receptor structure studies. 1 General structure of philanthotoxins PhTX- klm , where the numerals klm denote the number of methylene groups separating the nitrogen atoms (a, b, and c) in the polyamine side chain.…”
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.
“…Deprotection was performed via 37 as already described, yielding the tris(TFA) salt of 5-methyl-PhTX-334 (8). A similar pathway starting with 31 and leading, via 38؊40, to the tris(TFA) salt of 7-methyl-PhTX-334 (9), was performed as shown in Scheme 6. The tris(TFA) salts of 6؊9 were purified by preparative, reversed-phase HPLC and characterized by HRMS, 1 H and 13 C NMR spectroscopy.…”
Philanthotoxin-433 (PhTX-433) is a polyamine wasp toxin that antagonizes certain ionotropic receptors noncompetitively. Four analogues of PhTX-433, C-methylated in the polyamine chain, were synthesized from (RS)-1,3-butanediol, two diamine building blocks, and an activated/protected tyrosine derivative. Use of a phosphane reagent more bulky than trimethylphosphane gave a high intramolecular selectivity between primary and secondary hydroxy groups in the Fukuyama−Mitsunobu reaction. Thus, trimethylphosphane proved to be the only phosphane reagent that enabled alkylation of 2-nitrobenzenesulfonamides with a wide range of
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