Dimensions of the ion channel in neuronal nicotinic acetylcholine receptor as estimated from analysis of conformation-activity relationships of open-channel blocking drugs

Abstract

Relationship between the size of the molecule in the series of organic ions Et3+N--(CH2)5--+NR1R2R3 (Ri--alkyl or cycloalkyl substituents) and their abilities to block nicotinic acetylcholine receptors (AChRs) due to their open-channel blockade in the neurons of autonomic ganglia and in frog end-plate was analyzed. All low-energy equilibrium conformations of the drugs were calculated by the molecular mechanics method. A unique rectangular channel profile 6.1 x 8.3 A, for which the best correlation between blocking activity of the drugs and total population of their conformations being able to penetrate into the channel, was deduced from all those tested.

Interaction of d-Tubocurarine with Potassium Channels: Molecular Modeling and Ligand Binding

“…The pore size in ion channels can be probed by drugs whose dimensions are comparable with the pore width (Zhorov et al, 1991;Tikhonov and Zhorov, 1998). Such dimensions are characteristic of a well known curare alkaloid d-tubocurarine, which can be approximated by a parallelepiped of ϳ8.5 ϫ 11 ϫ 17 Å (Zhorov and Brovtsyna, 1993).…”

Efficiency of open channel blockers of neuronal nicotinic acetylcholine receptors as estimated from the structure/activity relationship

“…, (9) where D (i) is the absolute predicted blocking activity of the compound i; x (j) is the absolute WV of the fragment j of the calibration series, and F (j,i) is the PFR for the fragment j of the compound i.…”

“…Sets of such fragments were obtained for all conformers of each substance. The probability of existence C (i,k) of the conformer k of the substance i was calculated using the following equation [9]:…”

Blockade of ion channels as an approach to studying AMPA receptor subtypes

“…The ability of bis-ammonium compounds to block the ion channel of the acetylcholine receptor has long been known and has been studied in detail [13,50,61]. However, the members of this large family of compounds which have thus far been synthesized, with simple aliphatic radicals attached to nitrogen atoms, lack the ability to block the ion channels of glutamate receptors [39].…”