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Research ArticleNEUROPHARMACOLOGY

SSR591813, a Novel Selective and Partial α4β2 Nicotinic Receptor Agonist with Potential as an Aid to Smoking Cessation

C. Cohen, O. E. Bergis, F. Galli, A. W. Lochead, S. Jegham, B. Biton, J. Léonardon, P. Avenet, F. Sgard, F. Besnard, D. Graham, A. Coste, A. Oblin, O. Curet, C. Voltz, A. Gardes, D. Caille, G. Perrault, P. George, P. Soubrié and B. Scatton
Journal of Pharmacology and Experimental Therapeutics July 2003, 306 (1) 407-420; DOI: https://doi.org/10.1124/jpet.103.049262
C. Cohen
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O. E. Bergis
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F. Galli
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A. W. Lochead
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S. Jegham
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B. Biton
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J. Léonardon
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P. Avenet
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F. Sgard
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F. Besnard
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D. Graham
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A. Coste
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A. Oblin
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O. Curet
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C. Voltz
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A. Gardes
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D. Caille
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G. Perrault
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P. George
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P. Soubrié
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B. Scatton
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Abstract

(5aS,8S,10aR)-5a,6,9,10-Tetrahydro,7H,11H-8,10a-methanopyrido[2′,3′:5,6]pyrano[2,3-d]azepine (SSR591813) is a novel compound that binds with high affinity to the rat and human α4β2 nicotinic acetylcholine receptor (nAChR) subtypes (Ki = 107 and 36 nM, respectively) and displays selectivity for the α4β2 nAChR (Ki, human α3β4 > 1000, α3β2 = 116; α1β1δγ > 6000 nM and rat α7 > 6000 nM). Electrophysiological experiments indicate that SSR591813 is a partial agonist at the human α4β2 nAChR subtype (EC50 = 1.3 μM, IA =19% compared with the full agonist 1,1-dimethyl-4-phenyl-piperazinium). In vivo findings from microdialysis and drug discrimination studies confirm the partial intrinsic activity of SSR591813. The drug increases dopamine release in the nucleus accumbens shell (30 mg/kg i.p.) and generalizes to nicotine or amphetamine (10–20 mg/kg i.p.) in rats, with an efficacy approximately 2-fold lower than that of nicotine. Pretreatment with SSR591813 (10 mg/kg i.p.) reduces the dopamine-releasing and discriminative effects of nicotine. SSR591813 shows activity in animal models of nicotine dependence at doses devoid of unwanted side effects typically observed with nicotine (hypothermia and cardiovascular effects). The compound (10 mg/kg i.p.) also prevents withdrawal signs precipitated by mecamylamine in nicotine-dependent rats and partially blocks the discriminative cue of an acute precipitated withdrawal. SSR591813 (20 mg/kg i.p.) reduces i.v. nicotine self-administration and antagonizes nicotine-induced behavioral sensitization in rats. The present results confirm important role for α4β2 nAChRs in mediating nicotine dependence and suggest that SSR591813, a partial agonist at this particular nAChR subtype, may have therapeutic potential in the clinical management of smoking cessation.

Footnotes

  • This work was financially supported by the European Community Project (QLK6-CT-2000-00318). Accounts of these findings have been presented at the Society For Neuroscience: Biton B, Bergis OE, Moser PC, Galli F, Lochead AW, Jegham S, Cohen C, Perrault G, Avenet P, Claustre Y, Coste A, Caille D, George P, Soubrié P, Scatton B. SSR591813, a novel and selective partial nicotinic (α4β2) receptor agonist for smoking cessation: pharmacological profile. Program no. 811.6. 2002 Abstract viewer/Itinerary Planner. Washington, DC: Society for Neuroscience, 2002. Cohen C, Perrault G, Curet O, Bergis OE, Voltz C. Soubrie P, Scatton B. The selective α4β2 nicotinic receptor partial agonist, SSR591813, reduces nicotine dependance in rats. Program no. 811.5. 2002 Abstract viewer/Itinerary Planner. Washington, DC: Society for Neuroscience, 2002.

  • DOI: 10.1124/jpet.103.049262.

  • ABBREVIATIONS. nAChR, nicotinic acetylcholine receptor; DHβE, dihydro-β-erythroidine; HEK, human embryonic kidney; DMPP, 1,1-dimethyl-4-phenyl-piperazinium; ANOVA, analysis of variance; FR, fixed ration; IA, intrinsic activity; SSR591813, (5aS,8S,10aR)-5a,6,9,10-tetrahydro,7H,11H-8,10a-methanopyrido[2′,3′:5,6]pyrano[2,3-d]azepine; AHBT 94, (R)-5-(2-azetidinylmethoxy)-2-chloropyridine.

  • ↵1 C.C. and O.E.B. contributed equally to this work

    • Received January 17, 2003.
    • Accepted April 4, 2003.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 306 (1)
Journal of Pharmacology and Experimental Therapeutics
Vol. 306, Issue 1
1 Jul 2003
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Research ArticleNEUROPHARMACOLOGY

SSR591813, a Novel Selective and Partial α4β2 Nicotinic Receptor Agonist with Potential as an Aid to Smoking Cessation

C. Cohen, O. E. Bergis, F. Galli, A. W. Lochead, S. Jegham, B. Biton, J. Léonardon, P. Avenet, F. Sgard, F. Besnard, D. Graham, A. Coste, A. Oblin, O. Curet, C. Voltz, A. Gardes, D. Caille, G. Perrault, P. George, P. Soubrié and B. Scatton
Journal of Pharmacology and Experimental Therapeutics July 1, 2003, 306 (1) 407-420; DOI: https://doi.org/10.1124/jpet.103.049262

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Research ArticleNEUROPHARMACOLOGY

SSR591813, a Novel Selective and Partial α4β2 Nicotinic Receptor Agonist with Potential as an Aid to Smoking Cessation

C. Cohen, O. E. Bergis, F. Galli, A. W. Lochead, S. Jegham, B. Biton, J. Léonardon, P. Avenet, F. Sgard, F. Besnard, D. Graham, A. Coste, A. Oblin, O. Curet, C. Voltz, A. Gardes, D. Caille, G. Perrault, P. George, P. Soubrié and B. Scatton
Journal of Pharmacology and Experimental Therapeutics July 1, 2003, 306 (1) 407-420; DOI: https://doi.org/10.1124/jpet.103.049262
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