Abstract
In order to characterize the pharmacologic profile of DN-2327, an isoindoline benzodiazepine (BZD) receptor ligand, its interactions with Ro15-1788 and diazepam were analyzed in rodents. The anti-conflict action of DN-2327 in two conflict tests using rats, the punished water-lick conflict (Vogel conflict) and the punished bar-pressing conflict test, was completely attenuated by treatment with Ro15-1788. The anti-convulsive (pentylenetetrazol [PTZ] induced convulsion) effect of DN-2327 was also reduced by Ro15-1788. These results suggest that the anti-conflict and anti-convulsive actions of DN-2327 may be mediated via BZD receptors. On the other hand, DN-2327 only slightly affected the motor coordination in mice and rats, as estimated by the inclined screen test and the climbing test, respectively; however, the compound attenuated the motor incoordination produced by diazepam. Furthermore, the pentobarbital potentiating effect of diazepam was reduced by pretreatment with DN-2327 in mice. In the Vogel conflict test, additive effects were observed upon the concomitant administration of subeffective doses (5 mg/kg, PO) of DN-2327 and diazepam. DN-2327 at 20 mg/kg, PO, did not reduce but slightly potentiated the anti-conflict effect of the maximum effective dose of diazepam. For PTZ-induced convulsions, DN-2327, 0.5 and 20 mg/kg, PO, doses which produced partial and complete anti-convulsive effects, respectively, in rats did not reduce but increased additively the effects of diazepam. DN-2327 at 10 and 20 mg/kg, PO, doses which both produced partial anti-convulsive effects in mice, showed an additive effect with the partial effects of diazepam. Thus, DN-2327 differentially influenced the BZD receptors: it acted as an agonist with respect to the anti-conflict and anti-convulsive effects but as an antagonist with respect to the muscle relaxant and sedative effects of diazepam. These results suggest that DN-2327 possesses receptor agonist and antagonist properties for BZD receptors.
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References
Barone D, Colombo G, Glasser A, Luzzani F, Mennini T (1984) In vitro interaction of premazepam with benzodiazepine receptors in rat brain regions. Life Sci 35:365–371
Bennett DA, Petrack B (1984) CGS9896: a nonbenzodiazepine, nonsedating potential anxiolytic. Drug Dev Res 4:75–82
Bernard PS, Bennett DA, Pastor G, Yokoyama N, Liebman JM (1985) CGS9896: agonist-antagonist benzodiazepine receptor activity revealed by anxiolytic, anticonvulsant and muscle relaxation assessment in rodents. J Pharmacol Exp Ther 235:98–105
Blanchard JC, Julou L (1983) Suriclone: a new cyclopyrrolone derivative recognizing receptors labeled by benzodiazepines in rat hippocampus and cerebellum. J Neurochem 40:601–607
Brown CL, Martin IL, Jones B, Oakley N (1984) In vivo determination of efficacy of pyrazoloquinolinones at the benzodiazepine receptor. Eur J Pharmacol 103:139–143
Cooper SJ, Kirkham TC, Estall LB (1987) Pyrazoloquinolines: second generation benzodiazepine receptor ligands have heterogeneous effects. TIPS 8:180–184
File SE (1983) Sedative effects of PK9084 and PK8165, alone and in combination with chlordiazepoxide. Br J Pharmacol 79:219–223
Finney DJ (1944) The application of probit analysis to the results of mental test. Psychometrika 9:31–39
Gardner CR (1988) Pharmacological profiles in vivo of benzodiazepine receptor ligands. Drug Dev Res 12:1–28
Gardner CR (1989) Interpretation of the behavioral effects of benzodiazepine receptor ligands. Drugs of the Future 14:51–67
Gee KW, Yamamura HI (1982) A novel pyrazoloquinoline that interacts with brain benzodiazepine receptors: characterization of some in vitro and in vivo properties of CGS9896. Life Sci 30:2245–2252
Gee KW, Brinton RE, Yamamura HI (1983a) CK218872 antagonism of diazepam-induced loss of righting reflex: evidence for partial agonistic activity at the benzodiazepine receptor. Life Sci 32:1037–1040
Gee KW, Brinton RE, Yamamura HI (1983b) PK8165 and PK9084, two quinoline derivatives with anxiolytic properties, antagonize the anticonvulsant effects of diazepam. Brain Res 264:168–172
Geller I, Seifter J (1960) The effects of meprobamate, barbiturate,d-amphetamine and promazine on experimentally induced conflict in the rat. Psychopharmacologia 1:382–492
Klepner CA, Lippa AS, Benson DI, Sano MC, Beer B (1979) Resolution of two biochemically and pharmacologically distinct benzodiazepine receptors. Pharmacol Biochem Behav 11:457–462
Kockgether T, Schwarz M, Turski L, Sontag KH (1985) ZK91296, an anti-convulsant β-carboline which lacks muscle relaxant properties. Eur J Pharmacol 110:309–315
Koob GF, Braestrup C, Britton KT (1986) The effects of FG7142 and Ro15-1788 on the release of punished responding produced by chlordiazepoxide and ethanol in the rat. Psychopharmacology 90:173–178
Levitan ES, Schofield PR, Burt DR, Rhee LM, Wisden W, Kohler M, Fujita N, Rodriguez HF, Stephenson A, Darlison MG, Barnard EA, Seeburg PH (1988) Structural and functional basis for GABA-A receptor heterogeneity. Nature 335:76–79
Lippa AS, Coupet J, Greenblatt EN, Klepner CA, Beer B (1979) A synthetic non-benzodiazepine ligand for benzodiazepine receptors: a probe for investigating neuronal substrates of anxiety. Pharmacol Biochem Behav 11:99–106
Lippa AS, Meyerson LR, Beer B (1982) Molecular substrates of anxiety: clues from the heterogeneity of the benzodiazepine receptors. Life Sci 31:1409–1417
Martin IL, Brown CL, Doble A (1983) Multiple benzodiazepine receptors: structures in the brain or structures in the mind? A critical review. Life Sci 32:1925–1933
Mohler M, Okada T (1977) Benzodiazepine receptor: demonstration in the central nervous system. Science 198:849–851
Pellow S, File SE (1986) Evidence that the β-carboline, ZK91296, can reduce anxiety in animals at doses well below those causing sedation. Brain Res 363:174–177
Petersen EN (1987) Benzodiazepine receptor pharmacology: new vistas. Drugs of the Future 12:1043–1053
Petersen EN, Jensen LH, Honore T, Braestrup C, Kehr W, Stephens DN, Wachtel H, Seidelman D, Schmiechen R (1984) ZK91296, a partial agonist at benzodiazepine receptors. Psychopharmacology 83:240–248
Pritchett DB, Sontheimer H, Shivers BD, Ymer S, Kettenmann H, Schofield PR, Seeburg PH (1989) Importance of a novel GABA-A receptor subunit for benzodiazepine pharmacology. Nature 338:582–585
Quintero S, Henney S, Lawson P, Mellanby J, Gray JA (1985) The effects of compounds related to γ-aminobutyrate and benzodiazepine receptors on behavioural responses to anxiogenic stimuli in the rat: punished barpressing. Psychopharmacology 85:244–251
Sanger DJ (1986) Investigation of the actions of the benzodiazepine antagonists Ro15-1788 and CGS8216 using the schedule-controlled behavior of rats. Pharmacol Biochem Behav 25:537–541
Sanger DJ, Perrault G, Morel E, Joly D, Zivkovic B (1987) The behavioral profile of zolpidem, a novel hypnotic drug of imidazopyridine structure. Physiol Behav 41:235–240
Sieghart W (1983) Several new benzodiazepines selectively interact with a benzodiazepine receptor subtype. Neurosci Lett 38:73–78
Sieghart W (1985) Benzodiazepine receptors: multiple receptors or multiple conformations? J Neural Transm 63:191–208
Stephens DN, Kehr W, Schneider HH, Braestrup C (1984) Bidirectional effects on anxiety of β-carbolines acting as benzodiazepine receptor ligands. Neuropharmacology 23:879–880
Vogel JR, Beer B, Clody DE (1971) A simple and reliable conflict procedure for testing antianxiety agents. Psychopharmacologia 21:1–7
Wada T, Nakajima R, Kurihara E, Narumi S, Masuoka Y, Goto G, Saji Y, Fukuda N (1989) Pharmacologic characterization of a novel non-benzodiazepine selective anxiolytic, DN-2327. Jpn J Pharmacol 49:337–349
Williams M (1984) Molecular aspects of the action of benzodiazepine and non-benzodiazepine anxiolytics: a hypothetical allosteric model of the benzodiazepine receptor complex. Prog Neuropsychopharmacol Biol Psychiatry 8:209–247
Wood PL, Loo P, Braunwalder A, Yokoyama N, Cheney DL (1984) In vitro characterization of benzodiazepine receptor agonists, antagonists, inverse agonists and agonist/antagonists. J Pharmacol Exp Ther 231:572–576
Yokoyama N, Ritter B, Neubert A (1982) 2-Arylpyrazolo[4,3-c] quinolin-3-ones: novel agonist, partial agonist and antagonist of benzodiazepines. J Med Chem 25:337–339
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Wada, T., Fukuda, N. Pharmacologic profile of a new anxiolytic, DN-2327: effect of Ro15-1788 and interaction with diazepam in rodents. Psychopharmacology 103, 314–322 (1991). https://doi.org/10.1007/BF02244284
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DOI: https://doi.org/10.1007/BF02244284