Summary
Novelty: The 2R,4R,5S-isomer of 2-amino-4,5-(1,2-cyclohexyl)-7-phosphonoheptanoic acid (ACPA) is claimed. This isomer is said to be considerably more potent as an excitatory amino acid (EAA) antagonist than the racemic material previously disclosed in US4761405.
Biology: The prefered isomer of ACPA inhibited binding of 3H-CES-19755 to rat forebrain membranes with a similar efficacy to (±)-CPP and with at least ten-fold greater potency than other isomers of ACPA. It was at least twenty-five times more potent than other isomers in inhibiting NMDA-induced seizures in mice and showed a ratio of 30 for the ED50 in this test (1.05 mg/kg) to the TD50 (32mg/kg) for impairment of rotorod performance (corresponding ratio for ±-CPP is 4.5).
Chemistry: Enantioselective enzymatic hydrolysis of cis-cyclohex-4-ene-1,2-bis-(methylacetate) was the key step in the exemplified synthesis of the preferred 2R,4R,5S-isomer.
Structure: