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Pharmacological and behavioral profile of N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-6-chinolincarboxamide (EVP-5141), a novel α7 nicotinic acetylcholine receptor agonist/serotonin 5-HT3 receptor antagonist

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Abstract

Rationale and objective

Agonists of α7 nicotinic acetylcholine receptors (nAChRs) may have therapeutic potential for the treatment of cognitive deficits. This study describes the in vitro pharmacology of the novel α7 nAChR agonist/serotonin 5-HT3 receptor (5-HT3R) antagonist N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-6-chinolincarboxamide (EVP-5141) and its behavioral effects.

Results

EVP-5141 bound to α7 nAChRs in rat brain membranes (K i  = 270 nM) and to recombinant human serotonin 5-HT3Rs (K i  = 880 nM) but had low affinity for α4β2 nAChRs (K i  > 100 μM). EVP-5141 was a potent agonist at recombinant rat and human α7 nAChRs expressed in Xenopus oocytes. EVP-5141 acted as 5-HT3R antagonist but did not block α3β4, α4β2, and muscle nAChRs. Rats trained to discriminate nicotine from vehicle did not generalize to EVP-5141 (0.3–30 mg kg−1, p.o.), suggesting that the nicotine cue is not mediated by the α7 nAChR and that EVP-5141 may not share the abuse liability of nicotine. EVP-5141 (0.3–3 mg kg−1) improved performance in the rat social recognition test. EVP-5141 (0.3 mg kg−1, p.o.) ameliorated scopolamine-induced retention deficits in the passive avoidance task in rats. EVP-5141 (1 mg kg−1, i.p.) improved spatial working memory of aged (26- to 32-month-old) rats in a water maze repeated acquisition task. In addition, EVP-5141 improved both object and social recognition memory in mice (0.3 mg kg−1, p.o.).

Conclusions

EVP-5141 improved performance in several learning and memory tests in both rats and mice, supporting the hypothesis that α7 nAChR agonists may provide a novel therapeutic strategy for the treatment of cognitive deficits in Alzheimer's disease or schizophrenia.

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Abbreviations

A-582941:

2-Methyl-5-(6-phenyl-pyridazin-3-yl)-octahydro-pyrrolo[3,4-c]pyrrole

Aβ1–40 :

Amyloid peptide

ABBF:

N–[(3R)-1-Azabicyclo[2.2.2]oct–3–yl]–7–[2–(methoxy)phenyl]-1-benzofuran-2-carboxamide

ABT-107:

5-(6-[(3R)-1-Azabicyclo[2,2,2]oct-3-yloxy]pyridazin-3-yl)-1H-indole

ACh:

Acetylcholine

ANOVA:

Analysis of variance

AR-R17779:

(−)-Spiro[1-azabicyclo[2.2.2]octane-3,5′-oxazolidin-2′-one]

AZD0328:

(2′R)-Spiro-[1-azabicyclo[2.2.2]octane-3,2′(3′H)-furo[2,3-b]pyridine] d-tartrate

d1:

Discrimination index

d2:

Unbiased discrimination index

EVP-5141:

N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-chinolincarboxamide

EVP-6124:

(R)-7-Chloro-N-quinuclidin-3-yl)benzo[b]thiophene-2-carboxamide

GR65630:

3-(5-Methyl-1H-imidazol-4-yl)-1-(1-methyl-1H-indol-3-yl)-1-propanone

GTS-21:

3-(2,4-Dimethoxybenzylidene)anabaseine

5-HT:

Serotonin (5-hydroxytryptamine)

5-HT3R:

5-HT3 receptor

JN403:

(S)-(1-Aza-bicyclo[2.2.2]oct-3-yl)-carbamic acid (S)-1-(2-fluoro-phenyl)-ethyl ester

LSD:

Fisher's least significant difference post hoc test

LTP:

Long-term potentiation

MLA:

Methyllycaconitine

nAChR:

Nicotinic acetylcholine receptor

NFR:

Normal frog Ringer's solution

RG3487:

N-[(3S)-1-Azabicyclo[2.2.2]oct-3-yl]-1H-indazole-3-carboxamide hydrochloride

S 24795:

2-[2-(4-Bromophenyl)-2-oxoethyl]-1-methyl pyridinium

SEN12333:

5-Morpholin-4-yl-pentanoic acid (4-pyridin-3-yl-phenyl)-amide

SEM:

Standard error of the mean

SSR180711:

1,4-Diazabicyclo(3.2.2)nonane-4-carboxylic acid 4-bromophenyl ester

T1:

Trial 1

T2:

Trial 2

W-56203:

(R)-3′-(3-Methylbenzo[b]thiophen-5-yl)spiro-[1-azabicyclo[2,2,2]-octane-3,5′-oxazolidin]-2′-one, compound 23

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Acknowledgments

We gratefully acknowledge the assistance of P. Ammelung, D. Chodor, H. Dresen, K. Jentzsch, M. Keil, S. Kellermann, D. Klankers, and M. Kuster.

Conflict of interest

All authors were employed by Bayer Healthcare, Bayer Technology Services, or Bayer Central Research, respectively, at the time of the experiments. EnVivo Pharmaceuticals, Inc., has a world-wide license from BayerSchering Pharmaceuticals for various patents covering this and other compounds.

Author information

Author notes

  1. Frank G. Boess

    Present address: Lilly Deutschland GmbH, Bad Homburg, Germany

  2. Christina Erb

    Present address: Biotest AG, Dreieich, Germany

  3. Katrin Schnizler

    Present address: Aachen University Clinic, Aachen, Germany

  4. F. Josef van der Staay

    Present address: Emotion and Cognition Group, Department of Farm Animal Health, Veterinary Faculty, Utrecht University, Utrecht, The Netherlands

  5. Marja van Kampen

    Present address: UCB Biosciences GmbH, Monheim, Germany

  6. Welf-Burkhard Wiese

    Present address: Bayer CropScience AG, Alfred-Nobel-Str. 50, 40789, Monheim, Germany

Authors and Affiliations

  1. Pharma Research CNS, Bayer Healthcare AG, 42096, Wuppertal, Germany

    Frank G. Boess, Jean de Vry, Christina Erb, F. Josef van der Staay, Marja van Kampen & Gerhard König

  2. Medicinal Chemistry, Bayer Healthcare AG, 42096, Wuppertal, Germany

    Timo Flessner, Martin Hendrix & Joachim Luithle

  3. Bayer Technology Services GmbH Biophysics, Leverkusen, Germany

    Christoph Methfessel & Katrin Schnizler

  4. Bayer Central Research, 51373, Leverkusen, Germany

    Welf-Burkhard Wiese

  5. EnVivo Pharmaceuticals, Inc, 500 Arsenal Street, Watertown, MA, 02472, USA

    Gerhard König

Authors
  1. Frank G. Boess
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  2. Jean de Vry
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  3. Christina Erb
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  4. Timo Flessner
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  5. Martin Hendrix
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  6. Joachim Luithle
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  7. Christoph Methfessel
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  8. Katrin Schnizler
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  9. F. Josef van der Staay
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  10. Marja van Kampen
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  11. Welf-Burkhard Wiese
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  12. Gerhard König
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Corresponding author

Correspondence to Gerhard König.

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Boess, F.G., de Vry, J., Erb, C. et al. Pharmacological and behavioral profile of N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-6-chinolincarboxamide (EVP-5141), a novel α7 nicotinic acetylcholine receptor agonist/serotonin 5-HT3 receptor antagonist. Psychopharmacology 227, 1–17 (2013). https://doi.org/10.1007/s00213-012-2933-4

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  • DOI: https://doi.org/10.1007/s00213-012-2933-4

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