Opioid ligands with extraordinarily high mu-selectivity: dermorphin tetrapeptides containing thymine-modified alanine residues.

Four new [D-MetO2]dermorphin tetrapeptides with substituted N- and C-terminal groups and a thymine-modified alanine residue at position 4 were prepared and tested for their activity. All analogues were found to be mu-opioid receptor ligands. Two of them, H-Tyr-D-MetO-Phe-TalNHR (R = H, Ad) displayed an extremely high mu-opioid receptor selectivity comparable with that of the most mu-selective agonists among opioid peptides.

[Synthesis and biological activity of new analogs of beta-casomorphine-5]. / Sintez i biologicheskaia aktivnost' novykh analogov beta-kazomorfina-5.

Four new analogues of beta-cazomorphine-5 modified at the C-end with ethylenediamine- and glycine-containing derivatives were synthesized by the standard method of peptide chemistry (mixed anhydrides, carbodiimide, activated esters): H-Tyr-Pro-Phe-Pro-Gly-EtDA-Gly-II (I) H-Tyr-Pro-Phe-Pro-Gly-EtDA-Gly-Gly-II (II) H-Tyr-Pro-Phe-Pro-Gly-EtDA-Gly-Gly-CO-CH3 (III) H-Tyr-Pro-Phe-Pro-Gly-EtDA-Gly-Gly-CO-CH2-CH2-COOH (IV) The level of affinity and the degree of selectivity of the peptides towards the mu- and delta-opioid receptors of the rat brain lyophilized membranes were studied by the radioreceptor method. All the new peptides displayed analgetic activity, largely depending upon their structure.

[The pharmacokinetics of propranolol when used with the propercuten transdermal therapeutic system (experimental data)]. / Farmakokinetika propranolola pri primenenii transdermal'noi terapevticheskoi sistemy properkutena (éksperimental'nye dannye).

The pharmacokinetic studies of propranolol following the application of the propercuten transdermal therapeutic system were performed in conscious rabbits previously assigned to 3 groups. Different forms of propercuten (forte and mite) were used in different groups, different areas of its application being employed. Pulsed intravenous injections of propranolol were given to Group 1 rabbits to conduct another series of pharmacokinetic studies. The rate of drug administration to the systemic bed was 0.08 mg/h per cm propercuten. The constant injection rate was maintained during 5 days, but when propercuten was withdrawn the elimination time of propranolol was 24 hours.

[The mechanisms of the participation of the peptidergic systems in regulating respiratory center function]. / Nekotorye mekhanizmy uchastiia peptidergicheskikh sistem v reguliatsii funktsii dykhatel'nogo tsentra.

In experiments on different species of animals respiratory stimulating effects of naloxone, TRH and its analogue RGH 2202 during respiratory rhythmogenesis disturbances, evoked by hyperventilation of lungs, bleeding and intoxication with cyanides or opiates, were investigated. The role of opiate and NMDA receptors in respiratory centre function is discussed.

[Stimulation of respiration with Piladox in experimental and clinical conditions during administration of drugs for general anesthesia]. / Stimuliatsiia dykhaniia Piladoksom v éksperimente i klinike v usloviiakh primeneniia sredstv dlia obshchei anestezii.

Experimental and clinical studies of the agent Piladox (RGH 2202) were conducted. Experiments on animals (rats, rabbits, mice) demonstrated that Piladox possesses the property of restoring respiration inhibited by narcotic analgesics and some general anesthetics as well as the respiratory-de-priming effect of acute blood loss and is a more effective stimulator of the respiratory center than cordiamine (nikethamide) or corasol. Clinical study of Piladox in 75 patients showed that intravenous infusion of 1 mg/kg of the agent in the awakening period produced a stimulating effect on respiration through increase of its frequency and increase of the respiratory volume. The minute respiratory volume in this case was even greater than the initial values, whereas the CO2 content in the blood and expired air reached the initial level. The hemodynamic values in this period remained generally stable. Piladox does not change the antinociceptive effect of the narcotic analgesics and analgesia in the immediate postoperative period when combined general anesthesia is applied.

[The influence of piracetam on the effects of narcotic analgesics]. / Vliianie piratsetama na éffekty narkoticheskikh anal'getikov.

In experiments on white male mice there was studied the influence of piracetam (250-300 mg/kg) on the analgesic effect of ligands of different types of opioid receptors (morphine, 7.5 mg/kg, DADLE, 7.5 mg/kg, pentazocine, 15 mg/kg) and also on the action of morphine concerning the cardiovascular system and respiration. Piracetam was shown to possess the antagonistic properties with respect to some effects of morphine, however they are not of the universal character and do not depend on the interaction with a certain type of opioid receptors.

[The characteristics of the interaction of the thyroliberin analog RGH 2202 and narcotic analgesics]. / Osobennosti vzaimodeistviia analoga tiroliberina RGH 2202 i narkoticheskikh anal'getikov.

The effect of an thyroliberin analogue RGH 2202 on respiration inhibition induced by narcotic analgetics and on their antinociceptive action was studied in experiments on mice, rabbits and rats. RGH 2202 (10 mg/kg, intravenously) was found to exert no effect on the antinociceptive effect of morphine in mice and rabbits. Meanwhile, RGH 2202 in doses of 1 to 5 mg/kg intravenously abolished the respiration inhibition induced by fentanyl (0.02-0.07 mg/kg, intravenously) or morphine (10 mg/kg, intravenously) in rabbits and rats. After administration of RGH 2202 in doses of 10-40 mg/kg intravenously no significant changes of arterial blood pressure or heart rate were observed. The results obtained suggest that RGH 2202 may be used for relieving the inhibitory effects of narcotic analgetics on the respiratory centre during intoxication with these agents and in anesthesiological practice.

[Comparison of the opioid activity of a number of enkephalin and dermorphin analogs]. / Sravnenie opioidnoi aktivnosti riada analogov énkefalinov i dermorfina.

In search of selective ligands of opioid receptors there was synthetized a number of shortened dermorphin analogues containing nucleic amino acid substituents in positions 4 and 5 and also nucleic amino acid analogues of enkephalins. All synthetized analogues of enkephalins and dermorphin possess opioid activity revealed on preparations of the guinea pig ileum and the mouse vas deferens. Among the obtained analogues there were detected analogues exhibiting a high delta-agonistic (Tyr-D-Ala-Phe-Gly-DL-Tal-OH) or mu-agonistic (Tyr-D-Phe-Gly-Tal-Leu-OH) activity comparable with that for standard preparations DADLE and DAGO.

[Analgesic activity of nucleoamino acid analogs of neuropeptides injected intracisternally and intravenously in mice]. / Izuchenie anal'geticheskoi aktivnosti nukleoaminokislothnykh analogov neiropeptidov pri ikh intratsisternal'nom i vnutrivennom vvedenii mysham.

The antinociceptive activity of several enkephalin and kyotorphine analogues having nonproteinogenic nucleoamino acids: adenyl alanine, thyminyl alanine or uracilyl alanine in their structure was studied by the method of tail clip stimulation in mice. Kyotorphine and its analogues administered intracisternally to mice were found to inhibit the nociceptive responses only at doses similar to toxic ones. At the same time among nucleoamino acid analogues of enkephalins compounds were detected which possessed the antinociceptive activity not only at intracisternal administration but at intravenous injection as well. Some structure-activity relationships of the compounds tested are discussed.

[Changes in the properties of brain opiate receptors during the development of morphine tolerance in rats]. / Izmenenie svoistv opiatnykh retseptorov golovnogo mozga v usloviiakh privykaniia krys k morfinu.

The effects of prolonged administration of morphine on the properties of opiate receptors of rat brain were studied. For this purpose the isotherms of binding of labeled mu-, delta-, and chi-ligands--morphine, D-Ala2, D-Leu5-enkephalin and ethylketocyclazocine--with brain membrane preparations of morphine-tolerant rats as well as those of control animals were analyzed. For quantitative determination of dissociation constants of the ligand-receptor complexes (K) and receptor concentrations ([Q]), the difference and simulation methods were used. It was shown that the values of K and [Q] vary within broad ranges in individual animals, whereas the individual variations of the [Q]/[K] ratios in controls or in morphine-tolerant rats are not so significant. This suggests [Q]/K to be one of the basic criteria for a comparison of properties of opiate receptors in different groups of animals. The use of this criterion and of the simulation method demonstrated that the development of tolerance causes changes in the properties of delta-receptors (the [Q]/K ratio decreases by greater than 50%). Unlike delta-receptors, the tolerance has no appreciable effect on the properties of mu- or chi-receptors or on the superhigh affinity binding sites of the ligands tested.

[Potentiating action of bi- and trivalent metal salts on the analgesic effect of morphine]. / Potentsiruiushchee deistvie solei dvukh- i trekhvalentnykh metallov na anal'geticheskikh éffekt morfina.

It has been found that the metal salts MnCl2, NiCl2, GdCl3 and LaCl3 in doses up to 30, 20, 5 and 10 micrograms, respectively, potentiate the analgesic effect of intracisternally injected morphine (2 micrograms per mouse). The ability of the metal salts to potentiate the affinity of opiate ligands to the appropriate receptors is effectuated via interaction of metal cation with the specific opiate receptor site. It is suggested that one of the possible mechanisms of the potentiating effect of some metal salts on the morphine-induced analgesia involves the enhancement of morphine affinity for mu-receptors in the brain.

[Effect of haloperidol on the analgesic activity of opiate agonists administered intracisternally and intrathecally]. / Vliianie galoperidola na anal'geticheskuiu aktivnost' opiatnykh agonistov pri ikh intratsisternal'nom i intratekal'nom vvedenii.

The mu-agonist morphine more actively inhibited the complex reflex manifestations of pain responses (the Hafner test and hot plate) in mice as compared to the spinal pain reflexes (tail flick). The delta-agonist D-Ala2-D-Leu5-enkephalin (DADL) abolished the responses of both types in the same doses. Haloperidol potentiated the ability of morphine and DADL to inhibit nociceptive responses at the cerebral level. The potentiating effect of this neuroleptic on inhibition of spinal nociceptive responses by opiate agonists was only observed at a dose of 5 mg/kg. Haloperidol could also in some of the tests potentiate the antinociceptive effect of the kappa-agonist bremazocine and the sigma-agonist SKF 10.047, however their activity was significantly lower than that of morphine and DADL.

[Comparison of the analgetic activity of opioid peptides administered intracisternally and intravenously to mice]. / Sravnenie anal'geticheskoi aktivnosti opioidnykh peptidov pri ikh intratsisternal'nom i vnutrivennom vvedenii mysham.

Some of synthetic analogs of enkephalins, having protected bonds on the side of N- and C-terminals, were found to exhibit high analgetic activity when injected intracisternally. The analgetic action of enkephalin analogs was unchanged upon intravenous injection, which is accounted for by their resistance to proteolysis and the capacity to penetrate the blood-brain barrier. Based on an analysis of the drug ED50 ratios derived during intravenous and intracisternal injections an assumption might be made about low capacity of the test opioid peptides to reach opiate receptors in the central nervous system after systemic drug administration.

[Characteristics of the effect of ether, sodium thiopental, fentanyl and naloxone on respiration]. / Osobennosti vliianiia éfira, tiopental-natriia, fentanila i naloksona na dykhanie.

It has been demonstrated in experiments on rabbits that anesthetic ether sodium thiopental, phentanyl and leucine-enkephalin have different inhibitory effects on the activity of inspiratory and expiratory neurons in the medulla oblongata. Bemegrid recovers the activity of the respiratory center inhibited by all the substances under study whereas naloxone eliminates apnea induced by phentanyl or leucine-encephalin alone. Besides, it has been ascertained that naloxone effectively abolishes the inhibition of the respiratory center caused by hyperventilation in rats.

Correlation of hydrophobic character of opioid peptides with their biological activity measured in various bioassay systems.

Relative hydrophobicity of a series of enkephalin-like peptides has been studied by partitioning in the aqueous polymeric Ficoll-dextran biphasic system. The activities of the peptides in the guinea pig ileum, mouse vas deferens and rat brain receptor binding assay systems have been examined. The biological activities of the peptides in the two latter assays were correlated with their hydrophobic character. No correlation between the relative hydrophobicity of the compounds and their activity in the guinea pig ileum could be established. The correlations obtained appear to indicate that the drug-receptor interactions in the two bioassays occur under various conditions in regard to the local ionic composition at the membrane and/or the ionizable state of the receptor site. The activities of morphine and a number of similar drugs are described by a relationship different from that found for the peptides, which seems to support the multiple opiate receptor hypothesis.

[Morphine-like activity of the enkephalin analog Tyr-D-Ala-Gly-Phe-NH2]. / Morfinopodobnaia aktivnost' analoga énkefalinov Tyr--D-Ala--Gly--Phe--NH2.

The analgetic activity of the tetrapeptide enkephalin analog, its influence on the interneuronal transmission of excitation in various areas of the central nervous system and on opiate receptors of vas deferens were studied. The tetrapeptide was found to have a marked analgetic effect during intravenous injection to mice but to be less active than morphine. The tetrapeptide as well as morphine inhibited the impulse summation in rabbits and both spontaneous and bradykinin-induced neuronal activity in the rat sensory motor cortex. The tetrapeptide inhibited the contractions of isolated vas deferens in mice. The opiate antagonist naloxone eliminated both analgetic effect of the tetrapeptide and its inhibitory effect on the impulse summation, neuronal activity and contractions of vas deferens.

[Effect of leucine-enkephalin on the neuronal activity of the cerebral cortex]. / Vliianie leitsin-énkefalina na neironal'nuiu aktivnost' kory golovnogo mozga.

In the experiments on non-anesthetised, flaxedilimmobilized rats it has been shown that the injection of leucin-enkephalin (150 micrograms) into the lateral ventricle of the rat brain induces different changes in the activity of 21 test neurons of the sensomotor zone of the brain cortex. Spike discharges of 5 neurons decreased, while those of 11 neurons increased. Naloxone (2 mg/kg, i. v.) completely prevented both inhibiting and activating effects of leucin-enkephalin after repeated injections of this pentapeptide. Leucin-enkephalin failed to change the activity of 5 neurons.

[Effect of leucine-enkephalin on the interneuronal transmission of excitation]. / O vliianii leitsin-énkefalina na mezhneironnuiu peredachu vozbuzhdeniia.

In the experiments on non-anesthetized flaxedil-immobilized cats it has been shown that the injection of leucin-enkephalin (1 mg) into the lateral ventricle of the brain is followed by the inhibition of evoked potentials in the ventrolateral columns of the spinal cord and of segmental interneuronal transmission in the spinal cord as well as by the reduction of the amplitude of potentials in the S I zone of the brain cortex induced by the sciatic nerve stimulation. Naloxone (1 mg/kg, i.v.) prevented the effects of leucin-enkephalin. Methysergide pretreatment (2.5 mg/kg, i.p.) led to a decrease of leucin-enkephalin effect on the interneuronal transmission in the spinal cord. Leucin-enkephalin failed to change the amplitude of polysynaptic potentials of glosso-mandibular reflex integrated at the brain stem level.