Interaction between acetylcholine and other agonists at cholinoreceptive membrane of mollusc neurons.

The effect of pretreatment with agonists of various chemical structure on acetylcholine action at isolated Limnaea stagnalis neurones was studied. Threshold concentrations of monoquaternary agonists or dicholinic ester of adipinic acid increase and inhibit the responses to low and high acetylcholine concentrations respectively. In contrast, suberyldicholine and compound IEM-1054 (containing two charged ammonium groups in a molecule with an internitrogen distance of 2.0-2.2 nm) decrease the action of any acetylcholine concentration. The results are discussed in terms of the cooperativity model of acetylcholine receptors (AChR) and the hypothesis about regular arrangement of AChRs in the membrane, the so called 'C-16 structure'.

A new non-depolarizing myorelaxant with high activity and specificity.

The curare-like activity and mode of action of tercuronium (p,p"-bistriethylammonium-p-terphenyl dibenzen-sulphonate) have been investigated in experiments with cats, rabbits, mice and pigeons as well as with rat phrenic diaphragm preparations. The curare-like activity of tercuronium was higher than that of tubocurarine and was close to that of pancuronium bromide. The curare-like activity of tercuronium was higher than that of tubocurarine and was close to that of pancuronium bromide. The neuromuscular blocking doses (ED95) of tercuronium, (+)-tubocurarine and pancuronium in cats, for example, were 0.08 microM/kg, 0.4 microM/kg and 0.04 microM/kg respectively. The time of development and duration of action were similar to those of (+)-tubocurarine and pancuronium. Tercuronium is a nondepolarizing myorelaxant. In experiments with cats the antagonism of neostigmine (0.1 mg/kg) to tercuronium was more pronounced than in the case of (+)-tubocurarine, pancuronium or gallamine. Tercuronium affected neither the arterial pressure nor the heart rate when given in neuromuscular blocking doses. Tercuronium did not block transmission through autonomic ganglia and had no atropine-like action. Only a 10-fold increase in the dose of tercuronium produced the ganglion blocking effect in cats. Under artificial respiration, cats and rabbits tolerated tercuronium in a dose 200 times exceeding its myoparalytic dose. It is concluded that tercuronium is distinguishable from (+)-tubocurarine by its high neuromuscular blocking activity as well as by its specificity and more pronounced neostigmine antagonism.

[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.

[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.

[Effect of monoamines, heat shock and other factors on the binding of several neuropharmacologic preparations by sea urchin embryos]. / Vliianie monoaminov, teplovogo shoka i drugikh faktorov na sviazyvanie nekotorykh meirofarmakologicheskikh preparatov émbrionami morskikh ezhei

Early embryos of the sea urchins Arbacia lixula and Paracentrotus lividus being subjected to an osmotic or heat shock (10 min at 70 degrees C or higher) do not longer bind cytotoxic pharmaca and do not affect the sensitivity of normal indicator embryos to these drugs. After exposure for 10 min at 40 degrees C, the binding of neuropharmaca by embryos is not affected, although their ability to protect indicator embryos from the action of these neuropharmaca is inhibited 4--5 times. Serotonin and adrenaline inhibit the binding of neuropharmaca by 10--20%, while meterazine, noveryl and an amphetamine derivative--IEM-567--inhibit it by 50--60%. Antimycin A, rotenone and mercuric chloride do not affect the binding of neuropharmaca by sea urchin embryos.

[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.

[Selective action on hypophyseal gonadotropic function of a new compound from the group of aromatic series sulfur derivatives]. / Izbiratel'noe deistvie na gonadotropnuiu funktsiiu gipofoza novogo soedineniia iz gruppy sul'foproizvodnykh aromatic-heskogoriada.

Chronic experiments set up on rats showed the new original drug izm-931, a sulphoderivative of the aromatic series with a rigid molecular structure, to produce, depending upon its dose and reactivity of the hypothalamus-hypophysogonads, regulation system both stimulating and inhibiting gonadotropic effect. At the same time the drug produces neither peripheral nor estrogenic and antiestogenic action on the uterus and vaginal epithelium. The drug resembles but has a number of advantages over and differences with an earlier synthetized by the authors drug sigetin, whose pharmacological properties are close to the one under consideration. The synthesis and study of compounds of this kind are aimed at the search for new effective medicinal agents with an elective type of action on the gonadotropic function of the hypophysis which are of interest for the obstetric and gynecological practice. The present investigation is a new step towards solving this urgent problem of pharmacology in dealing with neuroendocrine regulation of the reproductive function.

[Experimental hypolipidemic and antiatherosclerotic activity of bisanions]. / Gipolipidemicheskaia i antiateroskleroticheskaia aktivnost' bisanionov v éksperimente.

Experiments on rabbits with experimental cholesterol atherosclerosis have shown bisanions :formula: see text.

[Effect of the structural characteristics of the alkyl derivatives of imidazole and pyrazole dicarboxylic acid diamides on body respiratory functions]. / Vliianie osobennostei struktury nekotorykh alkilproizvodnykh diamidov imidazol- i pirazoldikarbonovykh kislot na dykhatel'nye funktsii organizma.

It has been ascertained that alkyl derivatives of imidazoledicarboxylic acid diamides produce different effect on respiration and acid-base balance (ABB) of animal body. Antiphein and ethymisole stimulate respiration and change ABB. Ethirazol does not affect respiration, producing only insignificant changes in the respiratory component of ABB. Differences in the biological activity of the test drugs may be related to the structure or position of the alkyl radical in the heterocyclic ring.

[Characteristics of chemical structure of analogs of the antimalarial drug chloridine (pyrimethamine), detetermining their teratogenic properties]. / Osobennosti khimicheskogo stroeniia analogov antimaliariinogo preparata khloridina (primetamina), opredeliaiushchie ikh teratogennye svoistva

On an example of substituted 2,4-diaminopyrimidines containing at the 6th position hydrogen, alkyl radicals with a varying length of chains, ramified isoalkyl radicals and aromatic nuclei it is shown that the teratogenous activity is inherent only in some agents, being related to the chemical structure and conformation of the molecules. Accordingly, the principles of elective toxicity lying at the root of current chemotherapy may be extended also to teratology. From this it follows that there exists as a matter of principle the possibility of a purposeful synthesis of new medical compounds that would be devoid of teratogenous activity, but were endowed with valuable curative properties.

[Tercuronium, a new nondepolarizing myorelaxant with high activity and selective action]. / Terkuronii--novyi nedepoliarizuiushchii miorelaksant s vysokoi aktivnost'iu i izbiratel'nost'iu deistviia.

Tercuronium is p',p"-bis-triethylammonium-p-terphenyl dibenzosulfonate. As a curarelike agent tercuronium is 4--8 times as potent as (+)-tubocurarine. The time of the development and lasting of the blocking effect of tercuronium is approximately the same as that of (+)-tubocurarine. In a blocking dose tercuronium does not exert any effect either on the vegetative ganglia or arterial blood pressure. Partial blocking of the transmission through the vegetative ganglia as well as an insignificant and short-term drop of arterial blood pressure are recorded after intravenous injection of 10 myoparalytic doses of tercuronium. The antagonism of neostigmine against tercuronium was more pronounced than against (+)-tubocurarine, pancuronium and gallamine.

[Cholinomimetic activity of acetylcholine and sebacinyldicholine derivatives with differing cationic group structures]. / Kholinomimeticheskaia aktivnost' proizvodnykh atsetilkholina i sebatsinildikholina s razlichnoi strukturoi kationnoi gruppy

The intrinsic alpha activities and the D2 (frog, m, rectus abdominalis) concentrations were estimated for different acetylcholine and sebacinylcholine derivatives. So were also the A2 values for antagonists and the affinity constants Kc for some partial agonists. The results obtained disprove Paton's "rate-theory". The relationship between the cholinergic activity and the volume of cationic groups was studied and it could not possibly be explained by the steric hindrance alone. It is suggested that certain hydrophobic radicals of the cationic groups contact the receptor surface outside the anionic centre. Such contacts prevent the cholinoreceptor to change its conformation and thus inhibit the depolarization of the membrane. An approximate estimation of the anionic site dimensions is given.

[Cholinesterase hydrolysis of acetylcholine derivatives with different structures of the ammonium grouping]. / Gidroliz kholinésterazami proizvodnykh atsetilkholina s razlichnoi ammonievoi gruppirovki

15 acetoxyethylenammonium compounds are studied as substrates for acetylcholinesterase (ACE) from bovine erythrocytes and for butyrylcholinesterase (BCE) from horse serum. Substitution of methyl groups of the ammonium grouping with other radicals and incorporation of onium nitrogen in the cycle resulted in the decrease of the hydrolysis rate under the action of BCE and ACE, the effect of BCE being more pronounced. The rate of the hydrolysis of N-acetoxyethylene-N-methylpiperidine iodide in the presence of ACE was 65 times as much as in the presence of BCE. This compound is a new specific substrate of ACE. Dipropylmethyl derivative turned not to be a good substrate for both enzymes. Dibutylmethyl and pyridinic derivatives were not attacked by ACE and BCE. Kinetic analysis of the compounds listed is performed, taking account of non-productive sorbtion. Possible role of hydrofobic regions in the orientation of substrates on the active surface of ACE and BCE is discussed.