Bicyclic lactones derived from kainic acid as novel selective antagonists of neuroexcitatory amino acids.
The bicyclic [2S-(2 alpha,3 beta,4 beta)]-2-carboxy-4-(1-hydroxy-1-methylethyl)-3- pyrrolidineacetic acid delta-lactone (4), as well as its 4-[1-hydroxy-1-(iodomethyl)ethyl], 4-[1-hydroxy-1-(hydroxymethyl)ethyl], and 4-[1-hydroxy-1-[(phenyl-thio)methyl]ethyl] analogues, 6, 7, and 9, respectively, were designed and synthesized as potential selective antagonists of neuroexcitatory amino acids. When applied to rat brain slices, these lactones, which are chemically derived from kainic acid, inhibit the stimulation of Na+ fluxes induced by the neuroexcitants kainic acid and N-methyl-D-aspartic acid. Lactone 4 and the hydroxy lactone 7 block preferentially the response to N-methyl-D-aspartic acid, while the iodo lactone 6 and the phenylthio lactone 9 are mainly kainic acid antagonists. Total inhibitions can be obtained, half of the maximal effect being observed at lactone concentrations in the range of 0.2-3 mM.
D000596:Amino Acids / Q000037:antagonists & inhibitors*; D000818:Animals; D055598:Chemical Phenomena; D002621:Chemistry; D003342:Corpus Striatum / Q000187:drug effects; D066298:In Vitro Techniques; D007608:Kainic Acid / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D007783:Lactones / Q000138:chemical synthesis / Q000494:pharmacology; D009474:Neurons / Q000187:drug effects*; D011759:Pyrrolidines; D051381:Rats
D000596:Amino Acids; D007783:Lactones; D011759:Pyrrolidines; D007608:Kainic Acid