BIPHENYL-DERIVATIVES OF 2-AMINO-7-PHOSPHONOHEPTANOIC ACID, A NOVEL CLASS OF POTENT COMPETITIVE N-METHYL-D-ASPARTATE RECEPTOR ANTAGONISTS .1. PHARMACOLOGICAL CHARACTERIZATION IN-VITRO

omega-Phosphono-substituted a-amino acids have long been known to be a ntagonists at the N-methyl-D-aspartate (NMDA) receptor. D-2-Amino-5-ph osphonopentanoic (D-AP5) and D-2-amino-7-phosphonoheptanoic (D-AP7) ac ids are the ''prototype'' compounds of this kind. Insertion of a biphe nyl-moiety in the middle of the AP7 chain results in increased affinit y and reverses the enantioselectivity from a D- to an L-form preferenc e (Muller et al., (1992) Helv. Chim. Acta 75: 855-864). We describe he re a series of substituted biphenyl-AP7-derivatives, the most potent o f which have affinities (in a [H-3]CGP-39653 binding assay using nativ e and recombinant receptors) and potencies (antagonism of NMDA-induced depolarizations in a cortical wedge preparation; inhibition of glutam ate-stimulated [H-3]MK-801 binding under non-equilibrium conditions) i n the low nanomolar range. Structure-activity relationships show that hydroxy-substitution at the C5-atom in the AP7-chain as well as substi tution in the second phenyl ring with space filling (such as chloro-) groups in the para- and especially the ortho-position (extending the t orsion angle of the two rings) increase affinity and potency of these compounds. They have no relevant affinities for the strychnine-insensi tive glycine co-agonist site or the MK-801/PCP channel blocking site o n the NMDA receptor complex. AMPA- and kainate-induced responses were not affected by biphenyl-AP7-analqgues. These compounds also do not in teract with a number of other neurotransmitter receptor sites, and the y do not inhibit the uptake of [H-3]glutamate in rat brain synaptosome s. However, they display affinities in the (sub)micromolar range for a non-NMDA, non-AMPA, non-kainate binding site for [H-3]glutamate, meas ured in the presence of calcium chloride, the functional correlate of which has not yet been elucidated. Copyright (C) 1996 Published by Els evier Science Ltd.