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Dication Molecules as Tools for Studying Actylcholine and Glutamate Receptors (Review)

  • MOLECULAR-BIOLOGICAL PROBLEMS OF DRUG DESIGN AND MECHANISM OF DRUG ACTION
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Pharmaceutical Chemistry Journal Aims and scope

The review covers the pharmacochemical study of two receptor types, the neuronal nicotinate receptor and the glutamate receptor. The structure(activity relationship of dicationic blockers on the neuronal ion channel of the nicotinic acetylcholine receptor (nAChR) was studied to estimate the pore size in the cross section of the channel. A topographic model of the blocker binding site was proposed. It included two constrictions, a large one and a small one. The small constriction was located between the large one and the cytoplasmic end of the pore. The cross-sectional dimensions of the large and small constrictions that were estimated from the dimensions of the blockers were 6.1 × 8.3 Å and 5.5 × 6.4 Å, respectively; the spacing between the constrictions along the pore, ~7 Å. Acomparison of the topographic model with a molecular five-helix bundle model of the nAChR pore predicted that serine and threonine rings were the most probable candidates for the large and small constrictions, respectively. Replacement of aliphatic radicals on nitrogen atoms in dications by cyclic radicals led to the creation of a new class of compounds capable of blocking open ion channels of GluA1 α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors (Ca2+-permeable). It was found that N-methyl-D-aspartate (NMDA) receptor channels were blocked by both mono- and dicationic compounds while AMPA channels could be effectively blocked only by dicationic compounds of a certain length. The prospects for the use of combined (NMDA + AMPA) blockers as neuroprotective, anticancer, and antiviral agents were discussed.

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  1. Institute of Experimental Medicine, 12 Akad. Pavlova St., St. Petersburg, 197376, Russia

    V. E. Gmiro

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Translated from Khimiko-Farmatsevticheskii Zhurnal, Vol. 57, No. 6, pp. 3 – 17, June, 2023.

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Gmiro, V.E. Dication Molecules as Tools for Studying Actylcholine and Glutamate Receptors (Review). Pharm Chem J 57, 763–776 (2023). https://doi.org/10.1007/s11094-023-02951-9

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