Synthesis of the 2-amino-4-phosphonobutanoic acid analogues (E)- and (Z)-2-amino-2,3-methano-4-phosphonobutanoic acid and their evaluation as inhibitors of hippocampal excitatory neurotransmission.
The cyclopropyl compounds (Z)- and (E)-2-amino-2,3-methano-4-phosphonobutanoic acid, 5 and 6, respectively, were prepared as constrained analogues of 2-amino-4-phosphonobutanoic acid (AP4), a selective glutamate receptor ligand. A Horner-Emmons reaction of trimethyl N-(benzyloxycarbonyl)phosphonoglycinate with 2-(diethoxyphosphinyl)acetaldehyde gave the protected dehydroamino acids 9 and 10, which were individually subjected to the following sequence of reactions: cycloaddition of diazomethane, photoelimination of N2, and acid hydrolysis, to give 5 and 6, respectively. Extracellular recording techniques were used to evaluate the abilities of 5 and 6 to block evoked synaptic transmission in specific neuronal pathways of the rat hippocampal slice. In the lateral perforant path (LPP) 5 and 6 were equipotent and possessed IC50 values of 18 and 17 microM, respectively. In the medial perforant path (MPP), 6 (IC50 = 81 microM) was much more potent than 5 (IC50 = 1580 microM). In paired pulse experiments which differentiate presynaptic and postsynaptic inhibition, 5 and 6 enhanced the second response to the same extent as L-AP4, suggesting a presynaptic site of action for these compounds. In contrast, the cyclopentyl AP4 analogues 3 and 4 enhanced the second response to a lesser extent. It was concluded that the biologically active conformation of AP4 in the LPP is different than in the MPP. In order to explain the same potency of 5 and 6 in the LPP, it was postulated that the two analogues assume a conformation that allows their functional groups to occupy the same relative place in space. Molecular modeling showed that the best overlap was achieved when the alpha C-beta C-gamma C-P dihedral angle for 5 was in the range of 130 degrees to 180 degrees and that of 6 was in the range of -130 degrees to -180 degrees. The results suggest that the bioactive conformation of AP4 in the LPP is an extended one.
Department of Medicinal Chemistry, College of Pharmacy, University of Minnesota, Minneapolis 55455.
H B
HB
Kroona
N L
NL
Peterson
J F
JF
Koerner
R L
RL
Johnson
D000613:Aminobutyrates / Q000138:chemical synthesis* / Q000494:pharmacology; D000818:Animals; D004594:Electrophysiology; D006624:Hippocampus / Q000187:drug effects; D008297:Male; D018377:Neurotransmitter Agents / Q000037:antagonists & inhibitors*; D009943:Organophosphorus Compounds / Q000138:chemical synthesis* / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D000613:Aminobutyrates; D018377:Neurotransmitter Agents; D009943:Organophosphorus Compounds; C068881:2-amino-2,3-methano-4-phosphonobutanoic acid; C012729:2-amino-4-phosphonobutyric acid