The synthesis and pharmacology of novel excitatory amino acid mimetics

Joseph, M. (1984) The synthesis and pharmacology of novel excitatory amino acid mimetics. Doctoral thesis, City of London Polytechnic.


Glutamic and aspartic acids are considered to be potent excitatory amino acid neurotransmitters of vertebrates. Receptors for these amino acids may be sub-divided into three types: (i) Quisqualate/glutamate, (ii) N-methyl-D-aspartate (NMDA) and (iii) Kainate type. The aim of this project has been to develop specific mimetics which act only at one defined site. In particular, attention has been focused on the two former sub-groups.

It has been shown that 2-amino-5-phosphonopentanoic (APP) and 2-amino7-phosphonoheptanoic (APH) acids are very potent NMDA antagonists and anticonvulsants and in order to further the pharmacological study of this class of compound, efficient synthetic routes have been developed which afford the compounds in high overall yields. APB(2-amino-4-phosphono-butanoic acid), APP and APH can now be obtained in 10-50 g quantities which has permitted the evaluation of these compounds in a variety of animal models of epilepsy closely related to those in man. A study focused on photically stimulated seizures in the baboon has shown APP and APH to be particularly effective. This model is thought to be one of the closest to human seizures.

Quinolinic acid (Quin), an endogenous excitant and neurotoxin, may be classified as an NMDA type compound. The aim of this project has been to develop analogues of Quin, some of which may well be specific antagonists of NMDA. The higher homologue (1) of Quin has been s3rnthesised and has very recently been shown to be at least twelve times more potent than Quin as a neurotoxin. A series of homologues are to be synthesised, the synthesis of homologue (2) is now being completed. The peptide derivative (3) and its phosphonate analogue (4) have recently been synthesised and experiments are now in progress to determine their potency.

Tricholomic acid (TA)(5), an amino acid extracted from Tricholoma muscarium, has been suggested to be a very potent neuroexcitant of the quisqualate/glutamate sub-division by some Japanese workers. However, studies on this compound and the development of putative mimetics have been hindered by the lack of any reasonable synthetic route to TA. Such a route has now been devised and TA has been synthesised.

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