[A nondepolarizing muscle relaxant with rapidly developing and short-term action]. / Nedepoliarizuiushchii miorelaksant s bystro razvivaiushchimsia i kratkovremennym deistviem.

The pharmacological properties of the new nondepolarizing myorelaxant IEM-1213 and of its mixture with tercuronium were studied in experiments on anesthetized cats. Intravenous infusion of a blocking dose of IEM-1213 did not cause a change in the level of arterial pressure and blockade of the sympathetic ganglia but induced blockade of the heart muscarine receptors. The effect of IEM-1213 develops more rapidly and lasts for a shorter time than that of dithylin. Intravenous infusion of a mixture of IEM-1213 and tercuronium constituting 35 and 60% of the blocking dose of the former and, respectively, 35 and 20% of the blocking dose of the latter causes an effect similar in the time of its development to that of intravenous infusion of a total dose of IEM-1213 alone.

[Postsynaptic nondepolarizing muscle relaxants in clinical practice]. / Postsinapticheskie nedepoliarizuiushchie myshechnye relaksanty v klinicheskoi praktike.

Several postsynaptic nondepolarizing muscle relaxants are used today mainly for maintenance of muscular relaxation in surgical operations. They possess a highly selective effect on the cholinoceptors (CC) of the skeletal muscle postsynaptic membrane. Aminosteroid derivatives are important among them. The first to be suggested was pancuronium, and later pipecurium and the monoquaternary aminosteroid derivatives vecoronium and rocuronium. Highly selective muscle relaxants are atracurium and its isomers, cisatracurium in particular, as well as some atracurium derivatives: mivacurium and doxacurium. Tercuronium also has a highly selective effect on the CC of the skeletal muscles.

[Blockade of the ion channels of the skeletal muscle acetylcholine receptor]. / Blokada ionnykh kanalov retseptora atsetilkholina skeletnykh myshts.

The review deals with the literature data concerned with substances causing an effect on the ion channels of acetylcholine receptors in the skeletal muscles: local anesthetics, inhalation narcotics, postsynaptic muscle relaxants, and other drugs.

[The presynaptic action of muscle relaxants and cholinesterase inhibitors]. / Presinapticheskoe deistvie myshechnykh relaksantov i ingibitorov kholinesteraz.

This is a review of literature dealing with the action of relaxants and cholinesterase inhibitors on the skeletal muscles. They act on the presynaptic motor nerve endings in the muscles and, depending on the experimental conditions, increase or inhibit the release of acetylcholine by the endings. According to the literature data, two types of acetylcholine receptors (AchR) exist on the endings of a motor nerve. The neuronal type of AchR is related to a negative feedback mechanism and their blockade increases the release of acetylcholine by the motor nerve ending. Blockade of the muscular-type AchR is related to a positive, feedback mechanism and inhibits the release of acetylcholine.

[The inhibition of synaptic acetylcholinesterase by postsynaptic muscle relaxants]. / Tormozhnie sinapticheskoi atsetilkholinésterazy postsinapticheskimi myshechnymi relaksantami.

In experiments on narcotized cats records of contractions of the anterior tibial muscle in response to indirect stimulation showed that the mean dose of acetylcholine (Ach) blocking neuromuscular conduction and that of carbachole (Cch) for their injection into the corresponding femoral artery was 18.9 and 0.16 mumole/kg, respectively. In the period of partial blockade induced by depolarizing myorelaxants, the blocking dose of Ach reduced to a greater measure than that of Cch. Most nondepolarizing myorelaxants used in the experiment increased the blocking Ach dose less than the Cch dose. Benzoquinone possessing the highest antiacetylcholinesterase activity in vitro even reduced the blocking dose of Ach. This difference is apparently due to inhibition of the activity of synaptic acetylcholinesterase by the muscle relaxants.

[The effect of affinity on the type of action of ammonium compounds on skeletal muscle cholinoreceptors]. / Vliianie srodstva na tip deistviia ammonievykh soedinenii na kholinoretseptory skeletnoi myshtsy.

The dependence of the mode of action (agonist or antagonist) of ammonium compounds on the acetylcholine receptors (AcR) of frog skeletal muscles on their affinity for AcR was studied in experiments on musculus rectus abdominis of Rana temporaria frogs. The mode of action of the compounds proved to be dependent on the degree of the affinity and on the character of their intermolecular interactions with the receptors. The affinity of compounds of the polymethylene-bis-trimethylammonium series is determined by electrostatic and hydrophobic interaction with the AcR. In this case compounds with a low affinity constant (Ka) are poor antagonists, compounds with high Ka are strong antagonists, and compounds with intermediate Ka are partly agonists. Compounds whose affinity is determined not only by the electrostatic and hydrophobic but also by the dipole-dipole interaction (series D compounds) are pure and strong agonists.

Alkylating derivative of hexadecamethonium protects muscle synaptic acetylcholinesterase against inhibition.

The action of the alkylating derivative of hexadecamethonium on frog neuromuscular transmission was studied with the help of intracellular microelectrodes. Treatment of frog m. cutaneous pectoris-n. pectoralis preparations with the alkylating derivative of hexadecamethonium (0.5 microM) for 30 min led to an irreversible decrease in the amplitude of the end-plate potentials by 2.5-fold without a change of their latency period or quantal content. Such treatment led also to a considerable reduction of the anticholinesterase effects of neostigmine and of the organophosphorus irreversible inhibitor, armine. Thus, when applied to intact nerve-muscle preparations, neostigmine (2 microM) or armine (1 microM) increased the amplitude of end-plate potentials by 80-90%, and the rise time and half-decay time by about 2- to 3-fold. However, after the nerve-muscle preparations were pretreated with the alkylating derivative of hexadecamethonium (0.5 microM, for 30 min), the amplitude of end-plate potentials increased by 20-25%, rise time by 15-20% and half-decay time by 40-50% only. Investigation of muscle acetylcholinesterase activity, using the Ellman technique, showed that the alkylating derivative of hexadecamethonium diminished the sensitivity of the muscle acetylcholinesterase to inhibition without exerting its own inhibitory action.

[The level of cyclic nucleotides during spontaneous smooth-muscle contractions in the guinea pig]. / Uroven' tsiklicheskikh nukleotidov pri spontannykh sokrashcheniiakh gladkikh myshts morskoi svinki.

The relationships between isotonic tension and changes in cAMP and cGMP levels was studied in isolated preparations of the guinea-pig taenia coli and myometrium during spontaneous contractions. No significant changes in cyclic nucleotide levels were detected at any stage of the spontaneous contraction-relaxation cycle. The finding suggests that these changes play no significant role in the regulation of spontaneous contractions of the taenia coli and myometrium. However, other data obtained suggests the possibility of combined actions of the cGMP and phosphatidylinositols in control of smooth muscle motility during muscarine stimulation.

[Directions in the development of postsynaptic nondepolarizing muscle relaxants with rapidly developing action]. / O napravleniiakh razrabotki postsinapticheskikh nedepoliarizuiushchikh myshechnykh relaksantov s bystro razvivaiushchimsia deistviem.

The experiments on unconscious cats have shown that the myoparalytic effect of postsynaptic non-depolarizing myorelaxants which have a trimethylammonium cationic group develops more rapidly than that of their triethylammonium analogues. The compound IEM-1213 is given as an example of a trimethylammonium derivative with the rigid structure of the molecule having an unusual rapidly developed effect.

In search of new neuromuscular blocking drugs with quick onset and short duration of effect.

In experiments using cats the neuromuscular blocking effect of bis-trimethylammonium derivatives having a non-depolarizing mode of action had an onset of action shorter than that of their triethylammonium analogs. The difference in equieffective doses of neuromuscular blocking agents administered intravenously or intraarterially was less in the case of compounds with rigid molecules than that with flexible molecules. Results indicate that a more considerable portion of flexible substance absorbs on the 'site of loss' in blood vessels than for rigid compounds. This suggests that rigid molecules promote a faster achievement of effective concentration of a neuromuscular blocking agent at synapses. Proceeding from these data a bis-trimethylammonium derivative with a rigid molecule, IEM-1213, was synthesized and studied in cats.

Quest for agonist and antagonist selectivity at muscarinic receptors in guinea-pig smooth muscles and cardiac atria.

Potencies of 11 muscarinic agonists in eliciting contraction of smooth muscle in guinea-pig ileum, trachea, urinary bladder and uterus and in inhibiting the rate of contractions of cardiac atria were compared. While acetylcholine (ACh) was the most potent agonist on the ileum, uterus and cardiac atria, cis-L(+)-dioxolane was equally as potent as ACh on the ileum and more potent on the urinary bladder and trachea. Compared to ACh, methylfurmethide, oxotremorine, acetoxybut-2-inyl-trimethylammonium and cis-L(+)-dioxolane acted weakly on the atria. Aceclidine, arecoline and acetyl-beta-methylcholine displayed selectivity for the urinary bladder and pilocarpine for the tracheal and urinary bladder smooth muscles. Oxotremorine had very low activity on the uterus. The stereoselectivity of muscarinic ACh receptors (mAChRs) for cis-L(+)-and cis-D(-)-dioxolane was low in the urinary bladder and uterus and high in the ileum and trachea. Most antagonists showed little selectivity between different organs, but S(-)-phenylcyclohexylglycoloyl choline was 6 times more active on the urinary bladder than on the ileum and AF-DX 116 was 12-30 times more active on the atria than on the smooth muscles. Among the N-alkyl derivatives of benzilylcholine, the octyl derivative as 400 times more active on the ileum than on the atria, while among the N-alkyl derivatives of QNB, the N-decyl derivative was 41 times more active on the ileum. The observed differences in the potency of various agonists and their stereoisomers on different smooth muscles cannot be explained by differences in the accessibility of receptors or in receptor reserve.(ABSTRACT TRUNCATED AT 250 WORDS)

[The cholinomimetic activity of alkyltrimethylammonium compounds in experiments on the isolated mollusk neuron and on frog and chicken skeletal muscle]. / Kholinomimeticheskaia aktivnost' alkiltrimetilammonievykh soedinenii v opytakh na izolirovannom neirone molliuska i na skeletnoi myshtse liagushki i tsyplenka.

As revealed by contractile reaction of frog and chick muscles and by changes in the membrane current of isolated molluscan neurone, cholinomimetic activity of alkyltrimethylammonium compounds (ATMC) in the highest in drugs with 4 and 5 methylene groups in a molecule. The decrease in the activity with the decrease in the number of methylene groups was more evident in chick muscle; the decrease in the activity due to the increase in the number of these groups was most significant in experiments on molluscan neurone. Analysis of membrane current fluctuations showed that elementary current does not depend, whereas channel open time only slightly depends on the number of methylene groups in ATMC. However, with the increase of the number of methylene groups above 4, gradual decrease was observed in the ability of ATMC to increase at low (threshold) concentrations the membrane current (response) in the neurone. This decrease in the potency of ATMC correlated with the increase in Q10 value for neuronal response and calculated Q10 value for the reaction rate of ATMC with cholinoreceptor. The decrease in the activity of these ATMC is presumably due to a longer duration of complex formation with cholinoreceptor because of the higher energy barrier. ATMC with 8 and 9 methylene groups at high (saturating) concentrations elicited significantly smaller neuronal response with higher Q10 value. It is suggested that this phenomenon is due to a longer duration of complex formation with cholinoreceptor because of a higher energy cost.

[Determination of the Hill coefficient in the action of various agonists on the N-cholinoreceptors of the isolated mollusk neuron]. / Opredelenie koéffitsienta Khilla pri deistvii raznykh agonistov na N-kholinoretseptory izolirovannogo neirona molliuska.

The Hill coefficient (2.07-2.23) of the response to low concentrations of acetylcholine and its analogues was unrelated to their cholinomimetic activity and molecular structure. A much greater value (2.32) was found for the acetylcholine analogue without the ester oxygen. Lesser values (1.96 and 1.81) were found for suberildicholine and succinylcholine. These values seem to be underestimated as even their subthreshold concentrations were not low sufficiently to estimate the true value of their Hill coefficient. More than two agonist molecules seem to be necessary for the opening of the snail acetylcholine receptor channel.

[The reaction of the N-cholinoreceptors of the isolated neuron of the mollusk Planorbarius corneus to polymethylene-bis-trimethylammonium compounds]. / Reaktsiia N-kholinoretseptorov izolirovannogo neirona molliuska Planorbarius corneus s polimetilen-bis-trimetilammonievymi soedineniiami.

Experiments have been made on isolated giant neurones of the mollusc Planorbarius corneus using clamp technique at temperatures 10 and 20 degrees C. The effect of polymethylene-bis-trimethylammonium compounds with 7-18 methylene groups in the molecule (C7...C18) on N-cholinoreceptors with chloride ionic channels was investigated. All these drugs were found to be agonists. Their cholinomimetic activity depends on the number of methylene groups (up to a certain extent) in their structure. This finding stands true also for skeletal muscles of frog and chick, as it had been shown in our earlier experiments. Analysis of membrane current fluctuations showed that the elementary current, the channel opened time, temperature coefficient (Q10) of the neuronal response to application of an agonist and the calculated Q10 of the reaction rate of the agonist with cholinoreceptor did not significantly differ for C8...C18 from the reaction rate of the agonist with cholinoreceptor. As compared with C8, C12...C18 exhibited 30 ... 40 times higher cholinomimetic activity, all other parameters in them being similar. Presumably, this difference is explained by concentrating capacity of C12...C18 at the membrane site because of their higher hydrophobic properties.

[Factors affecting the cholinomimetic activity of alkyltrimethylammonium compounds in experiments on isolated neurons of the mollusk Planorbarius corneus]. / Faktory, opredeliaiushchie kholinomimeticheskuiu aktivnost' alkiltrimetilammonievykh soedinenii v opytakh na izolirovannom neirone molliuska Planorbarius corneus.

It has been shown that the elementary current is independent whereas the duration of channel opening is slightly dependent on the number of methylene groups (from 1 to 9) in the molecule of alkyltrimethylammonium compounds. However, substances with more than 4 methylene groups exhibit lower cholinomimetic activity (i.e. the ability to increase the membrane current) and higher values of Q10 for the reaction with cholinoreceptor. It is suggested that lower activity of these compounds is due to a low rate of formation of a complex with cholinoreceptor because of the higher potential energy barrier.

[Presynaptic action of tubocurarine during frequent stimulation of a motor nerve]. / Presinapticheskoe deistvie tubokurarina pri chastoi stimuliatsii dvigatel'nogo nerva.

The dependence of the end-plate potentials inhibition upon the prevention of the muscle twitches either by tubocurarine, or alpha-neurotoxin, or cutting of the fibers was studied during nerve tetanization in the frog isolated cutaneous pectoral muscles. The decrease in end-plate potentials in the course of tetanization was the strongest under the effect of tubocurarine. The latter seems to inhibit the quantum release of acetylcholine during the nerve tetanization.