title: 4-(Phosphonoalkyl)- and 4-(phosphonoalkenyl)-2-piperidinecarboxylic acids: synthesis, activity at N-methyl-D-aspartic acid receptors, and anticonvulsant activity.
abstract: A series of 4-(phosphonoalkyl)- and 4-(phosphonoalkenyl)-2-piperidinecarboxylic acids were synthesized, and their biological activity was assessed as competitive ligands for the NMDA receptor, both in vitro by using a receptor binding assay ([3H]CGS 19755 binding) and in vivo by using an NMDA seizure model in mice. The analogues were also evaluated in [3H]AMPA and [3H]kainate binding to assess their affinity for non-NMDA excitatory amino acid receptor subtypes. A number of these analogues show potent and selective NMDA antagonistic activity both in vitro and in vivo. Most notable are 4-(phosphonomethyl)-2-piperidinecarboxylic acid (1a) (CGS 19755) and the phosphonopropenyl analogue 1i, both of which show anticonvulsant activity in the 1-2 mg/kg ip range. With the aid of computer-assisted modeling, a putative bioactive conformation for AP-5 is hypothesized from the SAR data presented and a preliminary model for the antagonist-preferring state of the NMDA receptor is presented.
authors.affiliation: Research Department, CIBA-GEIGY Corporation, Summit, New Jersey 07901.
authors.forename: A J
authors.initials: AJ
authors.lastname: Hutchison
authors.forename: M
authors.initials: M
authors.lastname: Williams
authors.forename: C
authors.initials: C
authors.lastname: Angst
authors.forename: R
authors.initials: R
authors.lastname: de Jesus
authors.forename: L
authors.initials: L
authors.lastname: Blanchard
authors.forename: R H
authors.initials: RH
authors.lastname: Jackson
authors.forename: E J
authors.initials: EJ
authors.lastname: Wilusz
authors.forename: D E
authors.initials: DE
authors.lastname: Murphy
authors.forename: P S
authors.initials: PS
authors.lastname: Bernard
authors.forename: J
authors.initials: J
authors.lastname: Schneider
mesh_terms: D000818:Animals; D000927:Anticonvulsants / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D001224:Aspartic Acid / Q000031:analogs & derivatives* / Q000378:metabolism; D055598:Chemical Phenomena; D002621:Chemistry; D008297:Male; D051379:Mice; D016202:N-Methylaspartate; D010875:Pipecolic Acids; D010880:Piperidines / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D016194:Receptors, N-Methyl-D-Aspartate; D017981:Receptors, Neurotransmitter / Q000187:drug effects / Q000378:metabolism*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D000927:Anticonvulsants; D010875:Pipecolic Acids; D010880:Piperidines; D016194:Receptors, N-Methyl-D-Aspartate; D017981:Receptors, Neurotransmitter; D001224:Aspartic Acid; C053672:selfotel; D016202:N-Methylaspartate