Dication molecules as a tool for researching of Acetylcholine and glutamate receptors. Review.
V.E. Gmiro
Institute of Experimental Medicine, St. Petersburg, 197376 Russian
The review is devoted to the pharmacochemical study of two receptors types - the neuronal nicotinic receptor and the glutamate receptor. Structure-activity relationships of the dicationic blockers of the neuronal nicotinic acetylcholine receptor (nAChR) ion channel, have been studied to estimate the crosssectional dimensions of the channel pore. A topographic model of the binding site of the blockers was proposed. It incorporates two narrowings, a large and a small one. The small narrowing is located between the large one and the cytoplasmic end of the pore. The cross-sectional dimensions of the large and small narrowings estimated from the dimensions of the blockers are 6.1 × 8.3 Å and 5.5 × 6.4 Å, respectively, the distance between the narrowings along the pore being approximately 7 Å. A comparison of the topographic model with a molecular five-helix bundle model of nAChR pore predicts Serine and Threonine rings to be the most probable candidates for the large and small narrowings, respectively. Replacement of aliphatic radicals at nitrogen atoms in dicationic with cyclic radicals led to the creation of a new class of substances capable of blocking open ion channels of GluA1 AMPA receptors (Ca-permeable). It was found that NMDA channels are blocked by both mono- and dicationic compounds, while AMPA channels can 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 are discussed.
Сведения об авторах:
Гмиро Валерий Евгеньевич (Valery Gmiro) - ведущий научный сотрудник отдела нейрофармакологии Института экспериментальной медицины, 197376, Санкт-Петербург, ул. акад. Павлова, 12. Тел. +7-911-174-57-68. E-mail: gmiro2119@online.ru.