Modification of the philanthotoxin-343 polyamine moiety results in different structure-activity profiles at muscle nicotinic ACh, NMDA and AMPA receptors

Research output: Contribution to journalJournal articleResearchpeer-review

I R Mellor, T J Brier, F Pluteanu, K Strømgaard, A Saghyan, N Eldursi, M J Brierley, K Andersen, J W Jaroszewski, P Krogsgaard-Larsen, P N R Usherwood

Voltage-dependent, non-competitive inhibition by philanthotoxin-343 (PhTX-343) analogues, with reduced charge or length, of nicotinic acetylcholine receptors (nAChR) of TE671 cells and ionotropic glutamate receptors (N-methyl-D-aspartate receptors (NMDAR) and alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPAR)) expressed in Xenopus oocytes from rat brain RNA was investigated. At nAChR, analogues with single amine-to-methylene or amine-to-ether substitutions had similar potencies to PhTX-343 (IC(50)=16.6 microM at -100 mV) whereas PhTX-(12), in which both secondary amino groups of PhTX-343 were replaced by methylenes, was more potent than PhTX-343 (IC(50)=0.93 microM at -100 mV). Truncated analogues of PhTX-343 were less potent. Inhibition by all analogues was voltage-dependent. PhTX-343 (IC(50)=2.01 microM at -80 mV) was the most potent inhibitor of NMDAR. At AMPAR, most analogues were equipotent with PhTX-343 (IC(50)=0.46 microM at -80 mV), apart from PhTX-83, which was more potent (IC(50)=0.032 microM at -80 mV), and PhTX-(12) and 4,9-dioxa-PhTX-(12), which were less potent (IC(50)s>300 microM at -80 mV). These studies show that PhTX-(12) is a selective nAChR inhibitor and PhTX-83 is a selective AMPAR antagonist.
Original languageEnglish
JournalNeuropharmacology
Volume44
Issue number1
Pages (from-to)70-80
Number of pages11
ISSN0028-3908
Publication statusPublished - Jan 2003

    Research areas

  • Animals, Cell Line, Humans, Muscle, Skeletal, Nicotinic Antagonists, Oocytes, Patch-Clamp Techniques, Phenols, Polyamines, Rats, Rats, Wistar, Receptors, AMPA, Receptors, N-Methyl-D-Aspartate, Receptors, Nicotinic, Structure-Activity Relationship, Xenopus laevis

ID: 45823664