Excitant activity of methyl derivatives of quinolinic acid on rat cortical neurones.

Various synthetic analogues of quinolinic acid have been tested for agonist and antagonist properties when applied by microiontophoresis to neurones in the rat cerebral cortex. Quinolinic acid 2-methylester was a weak antagonist of N-methyl-D-aspartate (NMDA) and quinolinic acid, but also showed agonist activity, being about half as active as quinolinic acid. The excitant effects of the compound could be antagonized by the NMDA receptor blocker, 2-amino-7-phosphonoheptanoic acid (2APH). N-methyl-quinolinic acid 2, 3-dimethylester showed very weak agonist and antagonist activity. Homoquinolinic acid was a potent excitant of cortical neurones, being about five times more active than quinolinic acid and approximately equipotent with NMDA. The excitations were blocked by 2APH or its pentanoate analogue (2APV). Homoquinolinic acid 2-methylester was also active as an agonist. N-methyl-DL-glutamic acid was also tested, since homoquinolinic acid is a rigid analogue of this compound. Although it did cause excitation of 5 of the 16 units tested, N-methyl-glutamate was a weaker agonist than NMDA or homoquinolinate. Phthalic acid, ejected as an anion caused excitation of 14 out of 16 units. It is therefore concluded that the ring nitrogen of quinolinic acid is not essential for excitant activity. Since homoquinolinic acid is a rigid analogue of glutamic acid, but causes excitation by acting apparently on the NMDA receptor, the results are consistent with the suggestion that activation of the NMDA receptor may require the carboxyl groups to be held in a relatively extended configuration.