The ionic channel of neural nicotinic acetylcholine receptors is funnel-shaped.

Membrane currents evoked by iontophoretically applied acetylcholine were recorded from non-dissociated neurons of rat superior cervical ganglion using the whole-cell patch-clamp recording method. Blocking effects produced by a series of specially synthesized organic compounds, the blockers of the open channel of ganglionic nicotinic acetylcholine receptors, used as tools, were studied, and dimensions of the channel were deduced from correlation between the sizes of the blocking molecules and their blocking activities. Two channel cross-profiles were found, small and large, as approximated by the rectangles with the most probable dimensions 5.8 x 8.0 A and 7.0 x (8.4 - 9.0) A, at intra- and extracellular sides of the channel, correspondingly, in addition to the 6.1 x 8.3 A (medium) cross-profile found in our earlier work and localized between the two above. These findings indicate that the channel is funnel-shaped in the area where the open channel blockers are bound. The binding site is localized at the level of the medium cross-profile or between it and small cross-profile. The small cross-profile is probably a selectivity filter.

Comparative investigation of lipid and fatty acid composition of fish gills and mammalian lungs. A model of the membrane lipid component areas.

The lipid and fatty acid composition of gills and lungs were studied in 18 fish species and seven mammalian species. Different relationships among individual phospholipids and different molar ratios between phospholipids and cholesterol (2:1 in fish and 3:1 in mammals) were found. Conformational analysis of the main phospholipid and cholesterol molecules was carried out using a molecular mechanics method. The model of "one unit fragment of the membrane lipid component" accommodates 19 lipid molecules in fish and 42 in mammals. The areas of the molecule projections of the main phospholipids do not differ from each other by more than 2-3%. It may be suggested that the closely packed lipids in membranes of the aerohaematic barrier protect the organism of mammals from the high oxygen content in the environment.

[A theoretical conformational analysis of several substrates of cholinesterase having a cyclic ammonium group structure]. / Teoreticheskii konformatsionnyi analiz nekotorykh substratov kholinésterazy s tsiklicheskim stroeniem ammonievoi gruppirovki

Conformational possibilities of pirrolidine analogues of acetylcholine beta-(N-methyl pirrolidinium)-ethyl ester of acetic acid and beta-(N-ethyl pirrolidinium)-ethyl ester of acetic acid and beta-(N-ethyl pirrolidinium)-ethyl ester of acetic acid were investigated by the method of atomic potentials. The conformational energy was considered as a sum of non-bonded and electrostatical interactions, torsional energy and distortions of bond angles. It has been shown that the replacement of the nitrogen methyl group to ethyl group results in decrease of the average barrier height between two gauche conformations of the O--C--C--N fragment. Comparison of conformational properties of some cholinesterase substrates permit to draw a suggestion that the barrier height influences the rate of the enzymatic hydrolysis.

[Ion channel topography of the neuronal nicotinic acetylcholine receptor : pharmacochemical approaches]. / Topografiia ionnogo kanala neironal'nogo nikotinovogo kholinoretseptora: farmakokhimicheskie podxody.

Forty-three bisammonium ganglionic blockers were synthesized to study the structure of the ion channel of nicotinic acetylcholine receptor. The conformational parameters of these blockers were studied, and their effects toward the ganglionic transmission in situ on the sympathetic feline upper cervical ganglions and in vitro on the parasympathetic guinea-pig small intestine ganglions were determined. A model of the binding site for the bisammonium ganglionic blockers in the neuronal ion channel was proposed.

[Effect of ethymisole on long-term memory]. / O vliianii étimizola na dolgovremennuiu pamiat'.

Influence of ethymisol (bismethylamid of 1-ethylimidasol-4,5-dicarbonic acid) on learning and retention of habit was studied in experiments on rats by the method of active conditioned avoidance of electrical stimulation. At the same time optimal conformation form of the drug was determined by the method of proton magnetic resonance and by means of infrared spectra and theoretical conformation analysis. A single administration of ethymisol in the dose of 3 mg/kg reduced the deficit of the avoidance habit, when tested in 30 and 60 days following learning. A stable conformation of the ethymisol molecule with a planar arrangement of atoms of its heterocycle and amide groups was found in which the interaction of this substance with biological macromolecules was most active. The ethymisol effect on the long-term memory apparently results from a stable facilitation of synaptic transmission based on stabilization of spatial structure of biological macromolecules in the given conformation.

[The possible role of fatty acids and their conformation in the realization of the respiratory function and in the adaptations of fish gill membranes and of mammalian lungs]. / O vozmozhnoi roli zhirnykh kislot i ikh konformatsii v osushchestvlenii dykhatel'noi funktsii i v adaptatsiiakh membran zhabr ryb i legkikh mlekopitaiushchikh.

Fatty acid composition of major phospholipids has been studied in 12 fish and 7 mammalian species. Projections of the fatty acid pairs of these molecules on the plane parallel to the membrane surface have been computed. The projection area of two saturated acids was shown to look like the projection area of its "head", while substitution of one or two saturated acids to unsaturated ones increases the projection area 25%.

[Respiratory organ lipids in fishes and mammals. A model representation of the area of the lipid component]. / Lipidy organov dykhaniia ryb i mlekopitaiushchikh. Model'noe predstavlenie o ploshchadi lipidnoi komponenty.

Studies have been made on lipid composition of the gills in 19 species of fishes and of the lungs in 8 mammalian species. It was shown that the arbitrary "unit fragment" of the lipid component of the respiratory organs in all the investigated animals exhibits similar qualitative composition, but contains different quantity of lipid molecules, i. e. approximately 19 in fishes and 42 in mammals. Theoretical conformational analysis revealed predominant conformations of phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine, sphingomyelin and cholesterol; projections of these molecules on the surface which is parallel to membrane surface were composed. It was shown that projectional areas for the main phospholipid molecules differ only by 2-3%. These data indicate that the surface of a model of the lipid component in the membranes of respiratory organs in mammals is twice larger than in fishes. These differences presumably account for more effective oxygen transfer in mammals.

Conformational analysis of d-tubocurarine: implications for minimal dimensions of its binding site within ion channels.

All the minimum-energy conformations of d-tubocurarine were calculated by the method of molecular mechanics. The energy was minimized from 413 closed forms of the 18-member ring. The set of minimum-energy conformations includes 10 forms with energies less than 6 kcal/mol from the most stable one. Among the four lowest minimum-energy conformations, two forms correspond to those known from X-ray studies, whereas two conformations were not detected experimentally earlier. The flexibility of d-tubocurarine was estimated by calculating six paths of interconversion between the four lowest minimum-energy conformations. Using a molecular graphics technique, it was found that the most extended minimum-energy conformation of d-tubocurarine may fit in an ion channel of a rectangular profile of 8.7 x 11.2 A, while one tetrahydroisoquinoline head may fit a profile as small as 6.9 x 11.0 A. A possible model of d-tubocurarine location within the ion channel of the neuronal nicotinic acetylcholine receptor is suggested.

[Effect of diamide derivatives of imidazole- and pyrazoledicarboxylic acids on glyolysis indices depending on their structural characteristics]. / Vliianie proizvodnykh diamidov imidazol- i pirazoldikarbonovykh kislot na pokazateli glikoliza v zavisimosti ot osobennostei ikh struktury.

A study was made of the effect of diamide derivatives of imidazole- and pyrazole-dicarboxylic acids on blood glycolysis in rabbits depending on structural and conformational features of the molecules. It was shown that glycolysis is affected by the position and magnitude of an alkyl substituent in the heterocyclic part of the molecule. An essential role in the manifestation of metabolic activity is played by structural similarity of the test compounds to the adenine molecule.

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

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.

Architecture of the neuronal nicotinic acetylcholine receptor ion channel at the binding site of bis-ammonium blockers.

Structure-activity relationships of 56 pentamethylenbis-ammonium compounds, the blockers of the neuronal nicotinic acetylcholine receptor (nAChR) ion channel, have been studied to estimate the cross-sectional dimensions of the channel pore. The cat superior cervical sympathetic ganglion in situ and isolated guinea pig ileum were used to evaluate the potency of the compounds to block ganglionic transmission. Minimum-energy conformations of each compound were calculated by the molecular mechanics method. 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 x 8.3 A and 5.5 x 6.4 A, respectively, the distance between the narrowings along the pore being approximately 7 A. Most potent blockers would occlude the pore via binding to the channel at the levels of both narrowings. Less potent blockers are either too large or too small to bind to both narrowings simultaneously: large blockers would occlude the pore at the level of large narrowing, while small blockers would pass the large narrowing and occlude the pore at the level of small narrowing only. 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.