title: Modification of the philanthotoxin-343 polyamine moiety results in different structure-activity profiles at muscle nicotinic ACh, NMDA and AMPA receptors.
abstract: 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.
authors.affiliation: Division of Molecular Toxicology, School of Life and Environmental Sciences, University of Nottingham, Nottingham NG7 2RD, UK. ian.mellor@nottingham.ac.uk
authors.forename: I R
authors.initials: IR
authors.lastname: Mellor
authors.forename: T J
authors.initials: TJ
authors.lastname: Brier
authors.forename: F
authors.initials: F
authors.lastname: Pluteanu
authors.forename: K
authors.initials: K
authors.lastname: Strømgaard
authors.forename: A
authors.initials: A
authors.lastname: Saghyan
authors.forename: N
authors.initials: N
authors.lastname: Eldursi
authors.forename: M J
authors.initials: MJ
authors.lastname: Brierley
authors.forename: K
authors.initials: K
authors.lastname: Andersen
authors.forename: J W
authors.initials: JW
authors.lastname: Jaroszewski
authors.forename: P
authors.initials: P
authors.lastname: Krogsgaard-Larsen
authors.forename: P N R
authors.initials: PN
authors.lastname: Usherwood
mesh_terms: D000818:Animals; D002460:Cell Line; D006801:Humans; D066298:In Vitro Techniques; D018482:Muscle, Skeletal / Q000166:cytology / Q000378:metabolism; D018733:Nicotinic Antagonists / Q000494:pharmacology*; D009865:Oocytes / Q000378:metabolism; D018408:Patch-Clamp Techniques; D010636:Phenols / Q000737:chemistry / Q000494:pharmacology*; D011073:Polyamines / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D018091:Receptors, AMPA / Q000037:antagonists & inhibitors* / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011978:Receptors, Nicotinic / Q000187:drug effects* / Q000378:metabolism; D013329:Structure-Activity Relationship; D014982:Xenopus laevis
chemical_list: D018733:Nicotinic Antagonists; D010636:Phenols; D011073:Polyamines; D018091:Receptors, AMPA; D016194:Receptors, N-Methyl-D-Aspartate; D011978:Receptors, Nicotinic; C074003:philanthotoxin 343