The pharmacological selectivity of three NMDA antagonists

Three N-methyl-D-aspartate (NMDA) antagonists (+/-)2-amino-5-phosphonopentanoate (AP5), 3-((+/-)-2-carboxypiperazin-4-yl)propyl-1-phosphonic acid (CPP) and ((+/-)-5-methyl-10,11-dihydro-5H-dibenzo(a.d.)cyclohepten-5,10- imin e maleate) (MK-801) have been tested for selectivity against depolarization of motoneurones induced by carbachol, 5-hydroxytryptamine, noradrenaline and substance P in isolated immature rat spinal cord preparations. AP5 (400 microM) and CPP (50 microM) gave mean dose-ratios, for antagonism against NMDA, of 103 +/- 14.9 S.E.M. (eight preparations) and 34.1 +/- 1.9 S.E.M. (14 preparations). MK-801 (1 and 10 microM) was the most potent of the three antagonists yielding dose ratios greater than 100 after 120 min treatment. MK-801 potentiated responses induced by 5-hydroxytryptamine and noradrenaline given dose-ratios of 0.22 +/- 0.16 S.E.M. and 0.20 +/- 0.06 S.E.M., respectively (four preparations). The three antagonists produced no significant antagonism of the non-amino acid agonists (four preparations for each agonist) when dose-ratios against NMDA were at least 40. The observations support the use of these antagonists as tools to identify sites of excitatory amino acid-mediated transmission.