Characterization of retinal and hippocampal l-AP4 receptors using conformationally constrained AP4 analogues

In the past, the absence of useful 2-amino-4-phosphonobutanoic acid (AP4) analogues has hampered the pharmacological study and comparison of different systems which are sensitive to l-AP4. Several conformationally constrained AP4 analogues have now been synthesized: (E)- and (Z)-1-amino-3-phosphonocyclopentanecarboxylic acid [(E)- and (Z)-cyclopentyl AP4], and (E)- and (Z)-amino-3-phosphonocycolohexanecarboxylic acid [(E)- and (Z)-cyclohexyl AP4], and the recently synthesized cyclopropyl analogues (E)- and (Z)-2-amino-2,3-methano-4-phosphonobutanoic acid [(E)-and (Z)-cycloprophy; AP4]. Therefore, we have examined and report here the pharmacology of two retinal and two hippocampal l-AP4 sensitive systems using these analogues. In addition, the pharmacology of two kainic a acid/α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (KAIN/AMPA) pathways and one N-methyl-d-aspartate (NMDA) hippocampal pathways was examined. We found that the rank order potency of the l-AP4 sensitive systems were similar though not identical. The KAIN/AMPA and NMDA systems had a quite different rank order of potencies than the l-AP4 systems. These data suggest that the l-AP4 receptors in these different systems are structurally similar to each other and differ from both KAIN/AMPA and NMDA receptors.