Conformational aspects of the actions of some piperidine dicarboxylic acids at excitatory amino acid receptors in the mammalian and amphibian spinal cord.
A series of piperidine dicarboxylates (PDA) has been tested for excitatory amino acid agonist and antagonist activity and for synaptic depressant properties of the spinal cords of frogs and immature rats in vitro and of cats in vivo. The substances tested comprised (+/-)-cis-2,3-PDA, (+/-)-cis-2,4-PDA, (+/-)-cis-2,5-PDA, (+/-)-cis-2,6-PDA, (+/-)-trans-2,3-PDA, (+/-)-trans-2,4-PDA and both (+) and (-) forms of cis-2,3-PDA. Peak excitatory amino acid agonist activity was observed with (+/-)-trans-2,3- and (+/-)-trans-2,4-PDA. Excitatory amino acid antagonism and synaptic depressant activity was observed only with cis-dicarboxylates, this activity being greatest in the 2,3-analogue. The agonist actions of piperidine dicarboxylates were effectively depressed by the specific NMDA receptor antagonist, (-)-2-amino-5-phosphonovalerate and, where tested, also by D-alpha-aminoadipate and low concentrations of Mg2+. It was concluded that the major part of these agonist actions were mediated by NMDA receptors. The main structural feature of the NMDA agonist actions of these substances was considered to be their close relationship to N-alkyl-aspartic and glutamic acid molecules, with the trans arrangement of the respective 2,3- and 2,4-situated carboxyl groups promoting most effective interaction with the active sites of the NMDA receptor. (+/-)-Cis-2,3-PDA depressed excitatory responses induced by NMDA, kainate, quisqualate, (+/-)-trans-2,3-PDA and (+/-)-trans-2,4-PDA, or evoked by dorsal root stimulation. Both monosynaptic and polysynaptic excitation were susceptible to the depressant action of this substance. The (-) isomer of cis-2,3-PDA carried both excitatory amino acid agonist and antagonist activity and also the synaptic depressant properties observed with the racemic form of this substance. The (+) isomer showed little pharmacological activity. It is proposed that the structure-activity features of these heterocyclic amino acids indicate some of the conformational requirements for interaction with physiological excitatory amino acid receptors.
D000818:Animals; D002415:Cats; D003998:Dicarboxylic Acids / Q000494:pharmacology*; D008968:Molecular Conformation; D010875:Pipecolic Acids / Q000138:chemical synthesis / Q000494:pharmacology*; D010880:Piperidines / Q000494:pharmacology*; D011894:Rana pipiens; D011896:Rana temporaria; D051381:Rats; D011956:Receptors, Cell Surface / Q000187:drug effects / Q000378:metabolism*; D016194:Receptors, N-Methyl-D-Aspartate; D013045:Species Specificity; D013116:Spinal Cord / Q000502:physiology*; D013329:Structure-Activity Relationship; D013569:Synapses / Q000187:drug effects / Q000502:physiology
D003998:Dicarboxylic Acids; D010875:Pipecolic Acids; D010880:Piperidines; D011956:Receptors, Cell Surface; D016194:Receptors, N-Methyl-D-Aspartate; C029262:2,3-piperidinedicarboxylic acid