ISSN 1070-3632, Russian Journal of General Chemistry, 2018, Vol. 88, No. 2, pp. 159–187. © Pleiades Publishing, Ltd., 2018.
Original Russian Text © V.V. Ragulin, 2018, published in Zhurnal Obshchei Khimii, 2018, Vol. 88, No. 2, pp. 177–205.
In memory of Professor E.N. Tsvetkov
Phosphonic Aminocarboxylic Acids
V. V. Ragulin*
Institute of Physiologically Active Compounds, Russian Academy of Sciences, Severnyi proezd 1, Chernogolovka, 142432 Russia
Received November 9, 2017
Abstract—Methods of synthesis of phosphonic aminocarboxylic acids, ω-phosphonic analogs of monoamino-
dicarboxylic acids, are reviewed. Many of such compounds are ligands of ionotropic and metabotropic
glutamate receptors determining the phenomenon of information processing and communication in central
nervous system, important in view of prevention and treatment of Alzheimer, Huntington, and Parkinson
diseases and other socially important neurodegenerative and psychoneurological diseases as well as learning
and memory processes.
Keywords: ionotropic and metabotropic glutamate receptors, agonists, antagonisits, NMDA receptors,
phosphonic aminocarboxylic acids, АР5, АР7, СРР
Methods of synthesis and properties of amino-
phosphonic acids have been discussed in many reports
including reviews [1–3]. In view of this, here we focus
on a certain type of phosphorus-containing aminocar-
boxylic acids, ω-phosphonic analogs of monoamino-
dicarboxylic acids; phosphine oxides and phosphinic
aminocarboxylic acids (including phosphinotricine and
phosphinic pseudopeptides) are not considered.
Furthermore, we do not review general methods of
asymmetric synthesis of the said amino acids, since
they have been covered in . Methods of the enantio-
mers synthesis will be considered in regard to the
physiological activity or the preparation of new
phosphonic aminocarboxylic acids. The reviewed class
of compounds exhibits the potential of pronounced
physiological activity, making the review of methods
of synthesis of phosphonic aminocarboxylic acids a
topic of interest.
The interest to ω-phosphonic analogs of mono-
aminodicarboxylic acids is due to their physiological
activity as ligands of glutamate receptors determining
information processing and communication in central
nervous system, essential in view of prevention and
treatment of Alzheimer, Huntington, and Parkinson
diseases and other socially important neurodege-
nerative and psychoneurological diseases as well as
learning and memory related processes [4, 5].
L-Glutamate is a major excitative neurotransmitter
in the mammals brain, playing a key part in many
processes in central nervous system including patho-
physiological events like neurodegenerative diseases
and epilepsy. The action of glutamate is manifested via
a heterogeneous family of two types of receptors: iono-
tropic (iGluR) and metabotropic (mGluR) glutamate
receptors (Scheme 1). Ionotropic glutamate receptors
(iGluR) exhibit fast synaptic response via the ligand-
dependent ionic channels [4–9], and metabotropic
glutamate receptors (mGluR) of the exciting amino
acids are connected to the intracellular mediator
systems via the G-proteins and act as modulators in the
synaptic transmitting [4, 5, 10–14].
Key subtypes of ionotropic glutamate receptors of
central nervous system of the mammals are named
according to the known exogenic agonists: N-methyl-
D-aspartate (NMDA), kainic acid, quisqualic acid, and
acid (АМРА) [4–10].
NMDA receptors play the major part in
physiological and pathophysiological events in central
nervous system, including ischemic stroke, convulsions,
craniocerebral trauma, and pain. They are hetero-
tetramers of two subunits, NR1 and NR2 (more rarely
NR3); the NR2 subunit in its turn consists of four
subunits: NR2A, NR2B, NR2C, and NR2D [15, 16].