Antithrombotic Activity of a Novel Diazepino[1,2-α] Benzimidazole Derivative on Arterial Thrombosis Model in Rats without Concomitant Pathology and in Rats with Experimental Myocardial Infarction.

Antithrombotic activity of a novel tricyclic derivative of diazepino[1,2-α]benzimidazole (DAB-15) was examined on the model of arterial thrombosis developed in rats without concomitant pathology and in rats with experimental myocardial infarction. DAB-15 demonstrated high antithrombotic efficacy in modeled thrombosis of carotid artery in rats without the concomitant pathology surpassing that of the reference drugs acetylsalicylic acid and clopidogrel by 5.1 and 4.8 times, respectively. In rats with experimental noncoronary myocardial infarction, DAB-15 increased the thrombus formation time by 86.2% in comparison with experimental control level in non-treated rats with similar myocardial infarction.

GABAergic Mechanism of Anticonvulsive Effect of Chemical Agent RU-1205.

The study examined the effect of 9-(2-morpholinoethyl)-2-(4-fluorophenyl)imidazo[1,2-α] benzimidazole dihydrochloride (RU-1205) on the latency of seizures provoked by corazol, bicuculline, or picrotoxin. This agent (10 and 20 mg/kg) increased the seizure latency in the experimental models of epileptogenesis. The blockers of GABAA and GABA A -ρ receptors picrotoxin and (1,2,5,6-tetrahydropyridin-4-yl)methylphosphinic acid, respectively, were employed to study the effects of RU-1205 on electrical activity of somatosensory cortical neurons and on formation of pathological rhythms in the rat brain. RU-1205 inhibited the focal background rhythm and eliminated the epileptiform activity, which can be mediated by interaction with GABAA receptors.

Study of µ- and δ-Opioid Activities in Agents with Various κ-Receptor Selectivity.

A putative opioid agonist RU-1205 was ineffective within in vitro model of electrically induced contractions of rat ileum assessing the µ- and δ-opioid receptor pathways, while morphine inhibited these contractions in a dose-dependent and naloxone-reversible manners with EC50=2.6×10-7 M. In vivo experiments revealed no significant effects of RU-1205 on respiration and gastrointestinal tract contractile activity. In contrast, butorphanol decreased respiration rate by 25% (25-100 mg/kg) and slowed down the transit of labeled particles along the small intestine by 77.1% (1 mg/kg) and by 45.5% (10 mg/kg). Morphine-induced inhibition of peristalsis was dose-dependent with maximum effect (by 68.6%) observed in the dose of 10 mg/kg. It was concluded that the effects of RU-1205 are not related to activation µ- and δ-opioid receptors known to mediate the effects of non-selective opioid agonist morphine and agonist-antagonist butorphanol.

Antithrombotic Activity of DAB-15, a Novel Diazepinobenzimidazole Compound.

Antithrombotic activity of a new orally administered antiplatelet compound DAB-15 was compared to that of acetylsalicylic acid, ticlopidine, and clopidogrel in the experimental model of arterial thrombosis in rats caused by surface application of 50% ferric chloride (III) on the carotid artery. Compound DAB-15 exerted a dose-dependent antithrombotic effect and was superior to acetylsalicylic acid, ticlopidine and clopidogrel by 5, 7, and 4.9 times, respectively (by ED50). This necessitates studying of the action mechanism of this antiplatelet compound with consideration of its influence on different stages of the pathogenesis of platelet aggregation.

[NEPHROPROTECTIVE PROPERTIES OF 5-HT3 RECEPTOR BLOCKER RU-63 IN EXPERIMENTAL ACUTE RENAL FAILURE UNDER HYPERGRAVITY CONDITIONS].

The effective diuretic dose of 5-HT3 receptor blocker RU-63 (1 mg/kg) was found in experiments on white rats. It is established that the diuretic and saluretic effects of compound RU-63 increase on the background of impact of the gravitational factor. Compound RU-63 (1 mg/kg, subcutaneously) administered daily under hypergravity conditions (3 g in the direction of centrifugal force toward the kidneys) in animals with model ischemic acute renal failure increased excretory function of kidneys, glomerular filtration rate, and creatininuresis (on average by 180%; p < 0.05), and decreased serum creatinine, urinary excretion of protein, lactate dehydrogenase, and g-glutamyl transferase (on average by 49%; p < 0.05) as compared to the untreated control. Under similar conditions, the diuretic hydrochlorothiazide (in a dose of 20 mg/kg, intragastric) produced a more pronounced creatininuretic action than that of RU-63 (by 358%; p < 0.05).

Effect of a New Antioxidant Enoxifol on Platelet Aggregation and Blood Rheological Properties in Rats with Experimental Diabetes Mellitus.

Effect of a new antioxidant enoxifol exhibiting antiplatelet activity in vitro and in vivo on hemostasis parameters was assessed in laboratory rats with experimental diabetes mellitus. Gliclazide, a hypoglycemic agent with antiplatelet properties, and pentoxifylline, a preparation improving blood rheology, were used as the reference drugs. Enoxifol produced a pronounced inhibitory effect on platelet aggregation in rats with experimental diabetes comparable to the effect of gliclazide and decreased blood viscosity thus demonstrating a significant effect comparable to that of pentoxifylline. In view of the fact that oxidative stress is a pathogenetic components of vascular complications in diabetes, it can be assumed that improvement of hemostasis parameters under the effect of enoxifol is determined by its antiplatelet and antioxidant activities.

Antiepileptic Activity of a New Derivative of Benzimidazole RU-1205.

Antiepileptic activity of a new derivative of benzimidazole RU-1205 was studied on the model of pentylenetetrazole-induced generalized seizures in mice. Sodium valproate was used as the reference substance. RU-1205 was superior to sodium valproate by anticonvulsant activity (by 12 times) and therapeutic index (by 8.5 times). In contrast to sodium valproate, RU-1205 exhibited significant anticonvulsant activity on the model of pentylenetetrazole-induced kindling without tendency to resistance development.

[ANTIAGGREGANT ACTIVITY OF A NEW TRICYCLIC BENZIMIDAZOLE DERIVATIVE.]

The antiaggregant activity of a new benzimidazole derivative - 2,3,4,5-tetrahydro[1,3]diazepino[1,2-α]benzimidazole (DAB-15) has been investigated in vitro in comparison to reference drugs acetylsalicylic acid (ASA) and ticlid (ticlopidine) on the models of ASA, collagen, and epinephrine induced platelet aggregation in rabbits. It was established that DAB-15 exhibited dose-dependent antiaggregant activity. On the model of ASA-induced platelet aggregation, the effect of ADB-15 exceeded that of ASA and was slightly lower than that of ticlid. On the models of collagen, and epinephrine induced platelet aggregation, DAB-15 was reliably more active than the both reference drugs.

[COMPARATIVE STUDY OF THE INFLUENCE OF BENZIMIDAZOLE DERIVATIVE RU-1205, DIAZEPAM, AND SODIUM VALPROATE ON THE SEIZURE THRESHOLD, ANTICONVULSANT TOLERANCE, AND REBOUND EFFECTS.]

We have studied the effects of acute administration of benzimidazole derivative RU-1205 (9-(2-morpholinoethyl)-2-(4-fluorophenyl)imidazo(1,2-alpha)benzi- midazole), diazepam, and sodium valproate on the threshold for myoclonic and clonic seizures in response to i.v. infusion of pentylenetetrazole (PTZ) in mice. Furthermore, the effects of chronic administrations of RU-1205 and diazepam on the development of anticonvulsant tolerance and rebound phenomena were evaluated. The TID50 values (the dose of anticonvulsant required to increase the PTZ seizure threshold by 50%) of RU-1205, diazepam, and valproate for my- oclonic seizures were 7.9, 120.4, and 1.2 mg/kg (i.p.), respectively. TID50 of RU-1205, diazepam, and valproate for clonic seizures were 7.9, 116.9, and 1.3 mg/kg (i.p.), respectively The chronic administration of RU-1205 (31 mg/kg, i.p., 28 days) did not lead to the development of anticonvulsant tolerance or rebound effect after discontinuation of treatment. The anticonvulsant effect of diazepam (5 mg/kg, i.p., 28 days) in chronically treated mice was gradually abo- lished and the rebound effect was observed after the discontinuation of treatment.

NEUROPROTECTIVE PROPERTIES OF A NEW INHIBITOR OF NA+/H+ EXCHANGER (COMPOUND RU-1355) ON THE MODEL OF FOCAL ISCHEMIA IN RATS.

Primary neuroprotective properties of new inhibitor of Na⁺/⁺ exchanger (compound RU-1355) were established on the model of 60-min focal ischemia of the left middle cerebral artery followed by 24-h reperfusion in rats. Compound RU-1355 significantly (by 34%) decreased neurological symptoms, reduced (1.67 times) the growth of neuron-specific enolase level in serum, decreased (2.3 times) the size of the necrotic zone, and reduced by 59% (p <0.05) the degree of cerebral edema According to the results of morphometric, immunoassay, and neurological assessments of brain damage, compound RU-1355 is superior on ave- rage by 43.5% (p < 0.05) in comparison to selective NHE1 inhibitor zoniporide.

[Pharmacokinetic and analgesic properties of the injectable dosage form of a new imidazobenzimidazole derivative RU-1205 with kappa agonist activity].

Pharmacokinetic properties of imidazobenzimidazole derivative compound RU-1205 were investigated after subcutaneous administration to rabbits as a substance and a dosage form (lyophilisates for injection) at a dose of 25 mg/kg. The lyophilisate was characterized by high values of the relative bioavailability. In tests, the "hot plate" and "vinegar cramps" the dosage form and the substance exhibited the same analgesic effect.

Effect of Pyrrolobenzimidazole Derivative RU-792 on Experimental Brain Ischemia.

Compound RU-792 showed pronounced anti-ischemic activity and improved survival of rats with brain ischemia by normalizing parameters of spontaneous motor activity and reducing neurological deficit within 3 post-operative days being superior to the reference drug mexidol by this parameter. RU-792 inhibited the formation of conjugated dienes and malonic dialdehyde and increased activity of the antioxidant enzyme glutathione peroxidase thereby modulating the parameters of free radical oxidation in rats subjected to ischemia more effectively than mexidol.

[Pharmacokinetic and analgesic properties of tabletized dosage form of RU-1205-new imidazobenzimidazole derivative with kappa agonist activity].

The pharmacokinetic properties of a new imidazobenzimidazole derivative, compound RU-1205, were studied after peroral administration to rabbits at a dose of 50 mg/kg as a parent substance and in coated tablet dosage form. It was found that RU-1205 tablets are characterized by high values of the relative bioavailability (105.3 +/- 11.7%). The results of hot-plate and vinegar-cramp tests showed that both the dosage form and parent substance produced the same analgesic effect. Granulated RU-1205 produced maximum analgesic effect (138.8% relative to control) within 4-h investigation and retained higher analgesic activity compared to that of parent substance (on the average by 58%, p < 0.05) up to 12 h.

Effect of 5-HT(2A) receptor antagonists on blood flow in the carotid vessels upon elevation of serotonin level.

We studied the ability of predominantly 5-HT2A receptor antagonists to prevent a serotonin-induced change of blood flow in the carotid vessels of rats with experimental serotonin-induced spasm. Ritanserin, ketanserin, and 5-HT2A receptor antagonist RU-476 reduced the effect of serotonin on the blood fl ow velocity in the internal carotid artery by 2.3, 1.7, and 2.6 times, respectively.

Experimental study of the effect of a new antioxidant agent on learning and memory.

This work presents the results of studying the effect of a new antioxidant compound enoxyphol on learning and memory in rats.

Antiaggregant activity of a new benzimidazole derivative.

Antiaggregant activity of a new tricyclic benzimidazole derivative, RU-891 compound, was studied on the model of ADP-induced platelet aggregation in vitro and intravascular platelet aggregation in vivo. We evaluated the effect of this substance on blood coagulation potential. Antiaggregant agent acetylsalicylic acid was used as the reference drug. RU-891 produced a dose-dependent antiaggregant effect in vivo and in vitro that exceeded the effect of the reference drug. This compound did not modulate blood coagulation potential.

[Calcium-depended mechanism of the antiplatelet activity of benzimidazole derivative RU-891].

We have studied the effect of the new benzimidazole derivative RU-891, known to exhibit antiaggregant activity in vitro and in vivo, on the level of intracellular calcium ions in platelets of laboratory rabbits. Compound RU-891 was found to inhibit the thrombin-induced growth of intracellular calcium ion level in thrombocytes.This effect exceeded t he action o f reference d rugs and was not connected w ith the influence of RU-891 o n the potential-dependent c alci u m channels.

[The absolute bioavailability of benzimidazole derivative RU-1205 in rats].

Pharmacokinetics of morpholinoethylimidazobenzimidazole derivative RU-1205 with kappa-agonist activity have been studied. The pharmacokinetic parameters were determined upon intravenous (10 mg/kg), peroral, and subcutaneous (50 mg/kg) administration. It is established that RU-1205 substance has high bioavailability (44.17 and 56.03% upon peroral and subcutaneous introduction, respectively).

Antithrombogenic activity of antioxidant compounds.

Antithrombotic activities of enoxifol, a new antioxidant with antiaggregant activity demonstrated in vitro and in vivo, and antioxidant mexidol were compared on the rat model of arterial thrombosis induced by application of 50% ferric chloride. Acetylsalicylic acid (antiaggregant) served as the reference drug. All drugs exhibited dose-dependent antithrombotic activity. Enoxifol was more effective than mexidol, both drugs being more active than the reference drug (acetylsalicylic acid). Taking into account the pathogenesis of the thrombosis in this experimental model, we can hypothesize that the pronounced antithrombotic effect of enoxifol was due to its antiaggregant and antioxidant activities.

Antioxidant properties of pyrrolobenzimidazole derivative RU-792: experimental study.

We studied antioxidant activity of new derivative of pyrrolo[1,2-α]benzimidazole RU-792 and compared its effects on free radical processes with those of the reference antioxidant Trolox in four model free-radical systems. RU-792 had high antioxidant activity determined by its intrinsic antiradical properties. RU-792 was superior to Trolox by antioxidant activity in the models of Fe(2+)-induced chemiluminescence of lipids with 2,2-diphenyl-1-picrylhydrazyl and 2,2'-azino-bis-(3-ethylbenzothiazoline-6-sulfonic acid), but less effective in the model of luminol-dependent chemiluminescence.