Analogs of 2-amino-4-phosphonobutanoic acid (APB) as antagonists of excitatory neurotransmission in the mammalian central nervous system
The status of L-glutamate as an excitatory neurotransmitter in the mammalian central nervous system awaits elucidation due to the lack of potent and specific antagonists. The glutamate analog L-2-amino-4-phosphonobutanoic acid (L-APB) is a moderately potent antagonist of excitatory neurotransmission in the rate hippocampus (IC/sub 50/) = 2.5 ..mu..M), and this compound invites development of potentially more potent analogs. The directions of exploration in this research include: (1) modification of the dianionic capability on the side chain of APB; (2) variation of the spatial relationships between the charged groups on APB; (3) substitution of methyl groups for hydrogens at the N-, 2-, 3-, and 4-positions of APB in order to probe the steric tolerance of the APB recognition site; and (4) restriction of the conformations available to APB by including its structure in cyclic analogs. The biological activity of the analogs was measured electrophysiologically in the rat hippocampal slice. The ability of the APB analogs to displace DL-(/sup 3/H)-APB from a rat brain synaptosomal membrane preparation was also measured. The dianionic capability of the phosphonate moiety was not crucial for antagonist activity but appeared to contribute greatly to potency. An ..cap alpha..-relationship of the amino group to the carboxylate moiety appeared to be crucial for activity. The cyclic analogs were weaker than APB, although cyclopentyl analogs of APB did retain useful activity. The differences in potency noted for the APB analogs in these two assays suggested that the APB recognition sites in these two systems were not identical.
- Research Organization:
- Minnesota Univ., Minneapolis (USA)
- OSTI ID:
- 6701761
- Resource Relation:
- Other Information: Thesis (Ph. D.)
- Country of Publication:
- United States
- Language:
- English
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BIOLOGICAL FUNCTIONS
NEUROREGULATORS
CELL MEMBRANES
HIPPOCAMPUS
MAMMALS
RATS
TRACER TECHNIQUES
TRITIUM COMPOUNDS
AMINO ACIDS
ANIMALS
AUTONOMIC NERVOUS SYSTEM AGENTS
BODY
BRAIN
CARBOXYLIC ACIDS
CELL CONSTITUENTS
CENTRAL NERVOUS SYSTEM
DRUGS
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LABELLED COMPOUNDS
MEMBRANES
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551001* - Physiological Systems- Tracer Techniques