title: Structure-activity relationships of pentacycloundecylamines at the N-methyl-d-aspartate receptor.
abstract: Prompted by our interest in neuroprotective agents with multiple mechanisms of action, we assessed the structure-activity relationship of a series of pentacycloundecylamine derivatives previously shown to have both L-type calcium channel blocking activity and N-methyl-d-aspartate receptor (NMDAR) antagonistic activity. We utilized a functional assay to measure NMDAR channel block using (45)Ca(2+) influx into synaptoneurosomes. The cage amine 8-benzylamino-8,11-oxapentacyclo[5.4.0.0(2,6). 0(3,10).0(5,9)]undecane (NPG1-01) proved to be the most potent experimental compound with an IC(50) of 2.98microM, while 8-amino-pentacyclo[5.4.0.0(2,6).0(3,10).0(5,9)]undecane had the next most potent IC(50) of 4.06microM. Increasing the polycyclic cage size of NGP1-01 from a pentacycloundecane to a tridecane cage structure, but retaining the N-benzyl moiety decreased potency 10-fold, indicating a limitation on the volume of the cage that can be accommodated in the channel binding site. In the presence of NGP1-01, NMDA/glycine-induced maximal (45)Ca(2+) influx was attenuated by 34% with an insignificant effect on agonist potency. These results are consistent with uncompetitive antagonism for this group of compounds. Radioligand binding studies with [(3)H]MK-801 or [(3)H]TCP showed little or no displacement of these ligands by pentacycloundecylamines, suggesting that the latter compounds bind to a unique site in the NMDAR channel. The pentacycloundecylamines tested represent a novel group of NMDAR antagonists that have potential as therapeutic agents for neurodegenerative diseases including Parkinson's and Alzheimer's disease.
authors.affiliation: Department of Pharmaceutical Sciences, Northeastern Ohio Universities College of Pharmacy, Rootstown, OH 44272-0095, USA.
authors.forename: Werner J
authors.initials: WJ
authors.lastname: Geldenhuys
authors.forename: Sarel F
authors.initials: SF
authors.lastname: Malan
authors.forename: Jeffrey R
authors.initials: JR
authors.lastname: Bloomquist
authors.forename: Cornelis J
authors.initials: CJ
authors.lastname: Van der Schyf
mesh_terms: D000588:Amines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D001921:Brain / Q000187:drug effects; D016291:Dizocilpine Maleate / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D007473:Ion Channels; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D008958:Models, Molecular; D010622:Phencyclidine / Q000031:analogs & derivatives; D010880:Piperidines / Q000494:pharmacology; D011869:Radioligand Assay; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship; D013574:Synaptosomes / Q000187:drug effects*; D013876:Thiophenes / Q000494:pharmacology
chemical_list: D000588:Amines; D018691:Excitatory Amino Acid Antagonists; D007473:Ion Channels; D010880:Piperidines; D016194:Receptors, N-Methyl-D-Aspartate; D013876:Thiophenes; D016291:Dizocilpine Maleate; C012058:tenocyclidine; D010622:Phencyclidine