Cyclic analogs of 2-amino-4-phosphonobutanoic acid (APB) and their inhibition of hippocampal excitatory transmission and displacement of [3H]APB binding

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Abstract
Conformationally restricted analogues of 2-amino-4-phosphonobutanoic acid (APB, 2) were prepared where the structure of APB was incorporated into cyclopentane (3) or cyclohexane (4) rings. Hydrophosphinylation of the appropriate cycloalkenones followed by Strecker amino acid sythesis provided the described analogues. Assignments of the relative configurations for 3a (trans), 3b (cis) 4a (cis), and 4b (trans) were determined through 13C NMR studies. Compounds 3b, 4a, and 4b possessed low activity as inhibitors of excitatory synaptic field potentials in the rat hippocampal perforant path. Analogues 4a and 4b also showed little activity in displacing [3H]APB from synaptic plasma membranes. The cyclopentyl APB analogue 36, on the other hand, was extremely potent in inhibiting the binding of [3H]APB, possessing an IC50 = 4.7 .mu.M, thus giving further credence to the idea that the APB bindings site in the rat brain synaptosomal membrane preparation is not the same as the receptor mediating APB-induced inhibition of the lateral perforant path. Of the four cyclic APB analogues, 3a most resembled APP in its spectrum of biological activity. It showed significant potency (IC510 = 130 .mu.M) inhibiting lateral entorhinal projections to hippocampal granule cells. Analogous to APB, 3a also showed selectivity for the lateral perforant path over the median perforant path. Its activity in the radioligand binding assay paralleled its activity in inhibiting the lateral performant path. It thus appears that 3a comes closest to mimicking the active conformation of APB and suggests that a folded conformation wherein the amino and phosphonate moieties are in a cis relationship to one another may approximate the active conformation of APB.