Analgesic and Psychotropic Effects of a New Bradykinin Antagonist.

A bradykinin B1 receptors antagonist PAV-0056, an 1,4-benzodiazepin-2-one derivative, intragastrically administrated to mice at doses of 0.1 and 1 mg/kg causes analgesia in the "formalin test" not inferior to that of diclofenac sodium (10 mg/kg) and tramadol (20 mg/kg). PAV-0056 at doses of 0.1 and 10 mg/kg has no anxiolytic and central muscle relaxant effects in mice and does not damage the gastric mucosa in rats. Based on the results of the conditioned place preference test, PAV-0056 also does not induce addiction in mice.

Effect of 3-substituted 1,4-benzodiazepin-2-ones on bradykinin-induced smooth muscle contraction.

Biochemical properties of 3-substituted 1,4-benzodiazepine determined by the characteristics of their chemical structure. Influence of 3-substituted 1,4-benzodiazepin-2-ones on maximal normalized rate and amplitudes of isometric smooth muscle contraction in rats was investigated. Compounds MX-1775 and MX-1828 demonstrated the similar inhibition effect on bradykinin-induced contraction of smooth muscle like competitive inhibitor des-arg9-bradykinin-acetate to bradykinin B2-receptors. MX-1626 demonstrated unidirectional changes of maximal normalized rate and force of smooth muscle that proportionally depended on bradykinin concentration in the range 10-10-10-6 M. MX-1828 has statistically significant decrease of normalized rate of smooth muscle contraction for bradykinin concentrations 10-10 and 10-9 M by 20.7 and 8.6%, respectively, but for agonist concentration 10-6 M, this parameter increased by 10.7% and amplitude was reduced by 29.5%. Compounds MX-2011, MX-1785 and MX-2004 showed no natural effect on bradykinin-induced smooth muscle contraction. Compounds MX-1775, MX-1828, MX-1626 were selected for further research of their influence on kinin-kallikrein system and pain perception.

Affinities of gidazepam and its analogs for mitochondrial benzodiazepine receptors.

Mitochondrial benzodiazepine receptors (MBRs) participate in many physiological processes, such as calcium flow regulation, proliferative and respiratory cell functions, mitochondrial steroidogenesis and adaptational reactions to stress. We have found that the selective anxiolytic gidazepam has a higher affinity for CNS MBRs as compared to central benzodiazepine receptors. The ability of gidazepam to bind to MBRs probably underlies a wide spectrum of its pharmacological effects. We have studied affinities of gidazepam analogs for CNS MBRs in search for the ligands possessing higher affinity and selectivity. The experiments were carried out with male Wistar rats weighing between 200-220 g. Affinities of the investigated compounds were assessed on their ability to displace radioligand Ro5-4864 from its specific binding sites on MBRs of rat brain. Within the series of tested compounds three substances comparable on affinity with Ro5-4864 were found. Experimental results have shown that the presence of chlorine atom in o-position of 5-phenyl substituent leads to a 10 to 15-fold increase in affinity for CNS MBRs. We have also found that the essential contribution in affinity of the investigated series is brought by lipophilicity of substituent in IN-position. Our data may be useful in design and synthesis of novel potent selectively acting ligands of CNS MBRs.