Receptor binding profile and anxiolytic-type activity of deramciclane (EGIS-3886) in animal models

István Gacsályi, Éva Schmidt, István Gyertyán, Eero Vasar, Aavo Lang, Antti Haapalinna, M. Fekete, Jarmo Hietala, Erkka Syvälahti, Päivi Tuomainen, Pekka T. Männistö

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Abstract

The present series of experiments was done to characterize the properties of deramciclane, a new antiserotonergic drug, in both receptor binding studies in vitro and in a number of anxiolytic, antidepressant, and antidopaminergic tests in rodents. A striking property of deramciclane was its high affinity to both 5-HT(2A) and 5-HT(2C) receptors (K(i) = 8.7-27 nM/l). Deramciclane had also a moderate affinity to dopamine D2 and sigma receptors but did not interact with any of the adrenergic receptors. Deramciclane was active in several animal models predicting anxiolytic efficacy in humans. The active dose range of deramciclane was narrow in some tests, but generally the active dose range extended from 0.5 mg/kg (1.2 μmol/kg) to 10 mg/kg (23.9 μmol/kg). Statistically significant results were obtained in Vogel's test (1 mg/kg; 2.4 μmol/kg), social interaction (0.7 mg/kg; 1.7 μmol/kg), two-compartment box (3 mg/kg; 7.2 μmol/kg), and marble-burying tests (10 mg/kg; 23.9 μmol/kg). Although deramciclane as such was not active in the elevated plus maze, it antagonized the anxiogenic effect of the CCK agonist caerulein in this test, although significantly only at one dose (0.5 mg/kg; 1.2 μmol/kg). Deramciclane (1.4 and 14 mg/kg; 3.3 and 32.5 μmol/kg) was active in the learned helplessness paradigm. However, it had no antidepressant activity in tetrabenazine-induced ptosis or forced swimming test at ≤150 mg/kg (359 μmol/kg). Deramciclane elevated serum prolactin levels and brain dopamine metabolites (DOPAC, HVA) only at 20-40 mg/kg (48-96 μmol/kg). Deramciclane up to 40-100 mg/kg (96-239 μmol/kg) did not modify apomorphine-induced climbing, amphetamine-induced hyperlocomotion, or the conditioned avoidance reaction. Swimming-induced grooming was inhibited only by 50 mg/kg (112 μmol/kg) of deramciclane. Deramciclane reduced the motor activity at doses well above the established anxiolytic doses: ED50 18 mg/kg; 43 μmol/kg (rats) and 31.5. mg/kg; 75 μmol/kg (mice). Based on these results the anxiolytic-type selectivity of deramciclane appears satisfactory and to have a psychopharmacological profile of its own.

Original languageEnglish
Pages (from-to)333-348
Number of pages16
JournalDrug Development Research
Volume40
Issue number4
DOIs
Publication statusPublished - Apr 1997

Fingerprint

Anti-Anxiety Agents
Animals
Animal Models
Antidepressive Agents
deramciclane
Tetrabenazine
Learned Helplessness
Receptor, Serotonin, 5-HT2C
sigma Receptors
Ceruletide
3,4-Dihydroxyphenylacetic Acid
Grooming
Dopamine D2 Receptors
Calcium Carbonate
Apomorphine
Amphetamine
Interpersonal Relations
Metabolites
Prolactin
Adrenergic Receptors

Keywords

  • Elevated plus maze
  • Learned helplessness
  • Marble burying
  • Punished drinking
  • Serotonin 5-HT(2A) and 5-HT(2C) receptors
  • Swimming-induced grooming

ASJC Scopus subject areas

  • Organic Chemistry
  • Drug Discovery
  • Pharmacology

Cite this

Receptor binding profile and anxiolytic-type activity of deramciclane (EGIS-3886) in animal models. / Gacsályi, István; Schmidt, Éva; Gyertyán, István; Vasar, Eero; Lang, Aavo; Haapalinna, Antti; Fekete, M.; Hietala, Jarmo; Syvälahti, Erkka; Tuomainen, Päivi; Männistö, Pekka T.

In: Drug Development Research, Vol. 40, No. 4, 04.1997, p. 333-348.

Research output: Contribution to journalArticle

Gacsályi, I, Schmidt, É, Gyertyán, I, Vasar, E, Lang, A, Haapalinna, A, Fekete, M, Hietala, J, Syvälahti, E, Tuomainen, P & Männistö, PT 1997, 'Receptor binding profile and anxiolytic-type activity of deramciclane (EGIS-3886) in animal models', Drug Development Research, vol. 40, no. 4, pp. 333-348. https://doi.org/10.1002/(SICI)1098-2299(199704)40:4<333::AID-DDR7>3.0.CO;2-K
Gacsályi, István ; Schmidt, Éva ; Gyertyán, István ; Vasar, Eero ; Lang, Aavo ; Haapalinna, Antti ; Fekete, M. ; Hietala, Jarmo ; Syvälahti, Erkka ; Tuomainen, Päivi ; Männistö, Pekka T. / Receptor binding profile and anxiolytic-type activity of deramciclane (EGIS-3886) in animal models. In: Drug Development Research. 1997 ; Vol. 40, No. 4. pp. 333-348.
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AU - Vasar, Eero

AU - Lang, Aavo

AU - Haapalinna, Antti

AU - Fekete, M.

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