Springer Nature is making SARS-CoV-2 and COVID-19 research free. View research | View latest news | Sign up for updates

Pharmacological profile of a potential anxiolytic: AP159, a new benzothieno-pyridine derivative

  • 36 Accesses

  • 18 Citations


AP159 ([N-cyclohexyl-1,2,3,4-tetrahydrobenzo(b)thieno(2,3c)pyridine]-3-carboamide,hydrochloride) showed clear anti-conflict activity in rats in the absence of effects on muscle relaxation, potentiation of anesthesia (in mice) or anticonvulsant activity (in mice). This anticonflict effect was antagonized by treatment with Ro15-1788. By contrast with the deficits produced by diazepam, AP159 did not impair passive avoidance. The latter drug also improved scopolamine-induced amnesia in the same task. AP159 did not inhibit3H-flunitrazepam binding, but potently inhibited3H-8OH-DPAT binding. This compound increased serotonin and 5HIAA content of the midbrain raphe nuclei and of the amygdala centralis. AP159 has been shown to be a novel non-BZP anxiolytic agent with no side effects in laboratory animals; it could be a clinically effective anxiolytic agent.

This is a preview of subscription content, log in to check access.


  1. Broekkamp CL, Le Pichon M, Lloyd KG (1984) The comparative effects of benzodiazepines, progabine and PK9084 on acquisition of passive avoidance in mice. Psychopharmacology 83:122–125

  2. Bradford MM (1976) A rapid and sensitive method for the guantitation of microgram guantities of protein utilizing the principle of protein-dye binding. Anal Biochem 72:248–254

  3. Cerrito F, Raiteri M (1979) Serotonin release is modulated by presynaptic autoreceptors. Eur J Pharmacol 57:427–430

  4. Cook L, Davidson AB (1973) Effects of behaviorally active drugs in a conflict-punishment procedure in rats. In: Garattini S, Mussini E, Randall LO (eds) The benzodiazepines. Raven Press, New York, pp 327–345

  5. De Robertis E, Pellegrio De Irald A, Roriguez De Lores AG, Salaganicoff L (1962) Cholinergic and non-cholinergic nerve endings in rat brain-I. Isolation and subcellular distribution of acetylcholine and acetylcholineesterase. J Neurochem 9:23–35

  6. Eisenstein N, Iorio LC, Clody DE (1982) Role of serotonin in the blockade of muricidal behavior by tricyclic antidepressants. Pharmacol Biochem Behav 17:847–849

  7. Eison AS, Eison MS, Stanley M, Ribelet LA (1986) Serotonergic mechanisms in the behavioral effects of buspirone and gepirone. Pharmacol Biochem Behav 24:701–707

  8. Engel JA, Egbe P, Liljequist S and Soderpalm B (1989) Effects of amperozide in two animal models of anxiety. Pharmacol Toxicol 64:429–433

  9. File SE, Johnston AL, Pellow S (1987) Effects of compounds activity at CNS 5-hydroxytryptamine systems on anxiety in the rat. Br J Pharmacol 90:265–271

  10. Fujimoto M, Hashimoto S, Takahashi S, Hirose K, Hatakeyama H, Okabayashi T (1986) Detection and determination of active metabolites of 1-(2-o-chlorobenzoyl-4-chlorophenyl)-5-glycyl-aminomethyl-3-dimethylcarbamoyl-1H-1,2,4-tiazole hydrochloride dihydrate, (450191-S), in rat tissues, using a radioreceptor assay for benzodiazepines. Biochem Pharmacol 33:1645–1651

  11. Ghoneim MM, Mewaldt ST (1975) Effects of diazepam and scopolamine on strage, retrieval and organizational processes in memory. Psychopharmacology 44:257–262

  12. Goeders NE, Ritz MC, Kuhar MJ (1988) Buspirone enhance a benzodiazepine receptor binding in vivo. Neuropharmacology 27:275–280

  13. Gothert M, Schlicker E (1983) Autoreceptor-mediated inhibition of3H-5-hydroxytryptamine release from rat brain cortex slices by analogues of 5-hydroxytryptamine. Life Sci 32:1183–1191

  14. Gozlan H, Mestikawy EL, Pichat L, Glowinski J, Hamon M (1983) Identification of presynaptic serotonin autoreceptor using a new ligand3H-PAT. Nature 305:140–143

  15. Hall CS (1934) Emotional behavior in the rat. I. Defection and urination as means of individual differences in emotionality. J Comp Physiol Psychol 18:385–403

  16. Hall MD, Mestikawy EL, Emerit MB, Pichat L, Hamon M, Gozlan H (1985)3H-8-Hydroxy-2-(Di-n-propylamino)tetralin binding to pre-and postsynaptic 5-hydroxytriptamine sites in various regions of the rat brain. J Neurochem 44:1685–1696

  17. Heisterkamp DV, Cohen PJ (1975) The effect of intravenous premedication with lorazepam (Ativan), pentobarbital or diazepam on recall. Br J Anaesth 47:79–81

  18. Hiroshi S, Akira H, Tohru T, Mitsutaka N, Junki K (1987a) Pharmacological properties of SM3997: a new anxioselective anxiolytic candidate. Jpn J Pharmacol 45:493–500

  19. Hiroshi S, Tohru T, Noriyuki K, Akira H, Mitsutaka N, Junki K (1987b) The effect of SM3997, novel anxiolytic on brain monoamines. Jpn J Psychopharmacol 7:157–158

  20. Iversen SD (1984) 5HT and anxiety. Neuropharmacology 23:1553–1560

  21. Jarvik ME, Essaman WB (1960) A simple one trial learning situation for mice. Psychol Res 6:290–294

  22. Jensen A, Martinez JL, Vasquez BJ, McGaugh JL (1979) Benzodiazepines alter acquisition and retention of an inhibitory avoidance response in mice. Psychopharmacology 64:125–126

  23. Katharine HD, Milt T (1988) [3H]Spiroxatrine: a 5HT1A radio-rigand with agonist binding properties. J Neurochem 50:528–533

  24. Komisky HL, Cook TM, Lin CF, Hayton WI (1981) Impairment of lerning or memory in the mature and old rat by diazepam. Psychopharmacology 73:304–305

  25. Linnoila M, Mattila MJ (1973) Drug interaction on psychomotor skills related to driving: diazepam and alchol. Eur J Clin Pharmacol 5:186–194

  26. Linnoila M, Sarrio I, Maki M (1974) Effect of treatment with diazepam or lithium and alcohol on psychomotor skills related to driving. Eur J Clin Pharmacol 7:337–342

  27. Lippa AS, Coupet J, Greenblatt EN, Klepner CA, Bear A (1979) A synthertic non-benzodiazepine ligand for benzodiazepine receptors: a probe for investigating neuronal substrates for anxiety. Pharmacol Biochem Behav 11:99–106

  28. Lippa AS, Meyerson LR, Beer B (1982) Molecular substrates of anxiety: clues from the heterogeneity of benzodiazepine receptors. Life Sci 31:1409–1417

  29. Lister RG (1985) The amnesic action of benzodiazepines in man Neurosci Behav Rev 9:87–94

  30. Malick JB (1987) Neuropsychopharmacological drug development. In: Williams M, Malick JB (eds) Drug discovery and development. Human Press, Clifton, pp 115–149

  31. Palva ES, Linnolia I, Sarrio I, Mattila M (1979) Acute and subacute effects of diazepam on psychomotor skills: interaction with alchol. Acta Pharmacol Toxicol 45:257–264

  32. Pate JB, Ciofalo VB, Ioro LC (1979) Benzodiazepine blockade of passive avoidance task in mice: a state dependent phenomenon. Psychopharmacology 61:25–28

  33. Paxinos G, Watson C (1982) The rat brain in stereotaxic coordinates. Academic Press, New York

  34. Peterson RC, Ghoneim MM (1980) Diazepam and human memory: influence on acquisition, retrieval and state-dependent learning. Prog Neuropsychopharmacol 4:81–89

  35. Ray WF, Kenneth WP (1988) Effects of buspirone and its metabolite, 1-(2-pyrimidinyl)piperazine, on brain monoamines and their metabolites in rats. J Pharmacol Exp Ther 248:50–56

  36. Rowan MJ, Cullen WK, Moulton B (1990) Buspirone impairment of performance of passive avoidance and spatial learning tasks in rat. Psychopharmacology 100:393–398

  37. Soderpalm B, Engel JA (1989) Does the PCPA induced anticonflict effect involve activation of the GAGAA/benzodiazepine chloride ionophor receptor complex? J Neural Transm 76:145–153

  38. Sofia RD (1969) Effects of centrally active drugs on experimentally induced aggression in rodents. Life Sci 8:705–716

  39. Soubrie P, Simon P, Boissier JR (1976) An amnesic effect of benzodiazepines in rats? Experimentia 32:359–360

  40. Taylor DP, Eison MS, Riblet LA, Vandermaelen (1985) Pharmacological and clinical effects of buspirone. Pharmacol Biochem Behav 23:687–694

  41. Tsuneyuki Y (1989) Pharmacological properties of 5HT receptor related anxiolytics. Jpn J Neuropsychopharmacol 11:709–719

  42. Ueki S, Yamamoto T, Kataoka Y (1988) Muricide of the rat as an animal model of depression for the nonclinical evaluation of the antidepressants. In: Takagi H, Omura Y, Ito M, Otsuka M (eds) Biowarning system in the brain. Naito Foundation Symposium, University of Tokyo Press, pp 261–273

Download references

Author information

Correspondence to Tadashi Nagatani.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Nagatani, T., Yamamoto, T., Takao, K. et al. Pharmacological profile of a potential anxiolytic: AP159, a new benzothieno-pyridine derivative. Psychopharmacology 104, 432–438 (1991). https://doi.org/10.1007/BF02245645

Download citation

Key words

  • AP159
  • Anxiolytic
  • 5HT1A receptor
  • Anti-amnesia
  • Rat
  • Mouse