title: SSR591813, a novel selective and partial alpha4beta2 nicotinic receptor agonist with potential as an aid to smoking cessation.
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 alpha4beta2 nicotinic acetylcholine receptor (nAChR) subtypes (Ki = 107 and 36 nM, respectively) and displays selectivity for the alpha4beta2 nAChR (Ki, human alpha3beta4 > 1000, alpha3beta2 = 116; alpha1beta1deltagamma > 6000 nM and rat alpha7 > 6000 nM). Electrophysiological experiments indicate that SSR591813 is a partial agonist at the human alpha4beta2 nAChR subtype (EC50 = 1.3 micro M, 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 alpha4beta2 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.
authors.affiliation: Central Nervous System Research Department, Sanofi-Synthelabo Research, 31 avenue Paul Vaillant-Couturier, 92220 Bagneux, France. caroline.cohen@sanofi-synthelabo.com
authors.forename: C
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authors.lastname: Cohen
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authors.lastname: Bergis
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authors.lastname: Galli
authors.forename: A W
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authors.lastname: Lochead
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authors.lastname: Jegham
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authors.lastname: Biton
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authors.lastname: Leonardon
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authors.lastname: Avenet
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authors.lastname: Besnard
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authors.lastname: Graham
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authors.lastname: Coste
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authors.lastname: Curet
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authors.lastname: Voltz
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authors.lastname: Gardes
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authors.lastname: Caille
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authors.lastname: Perrault
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mesh_terms: D000818:Animals; D001381:Azepines / Q000627:therapeutic use*; D001522:Behavior, Animal / Q000187:drug effects; D001831:Body Temperature / Q000187:drug effects; D001921:Brain / Q000378:metabolism; D002319:Cardiovascular System / Q000187:drug effects; D002478:Cells, Cultured; D003913:Dextroamphetamine / Q000494:pharmacology; D004193:Discrimination Learning; D004347:Drug Interactions; D006576:Heterocyclic Compounds, 4 or More Rings / Q000627:therapeutic use*; D006801:Humans; D008297:Male; D008464:Mecamylamine / Q000494:pharmacology; D017551:Microdialysis; D009043:Motor Activity / Q000187:drug effects; D009538:Nicotine / Q000494:pharmacology; D018722:Nicotinic Agonists / Q000627:therapeutic use*; D009865:Oocytes / Q000187:drug effects / Q000378:metabolism; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D011978:Receptors, Nicotinic / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D012646:Self Administration; D012907:Smoking / Q000188:drug therapy*; D016540:Smoking Cessation; D013375:Substance Withdrawal Syndrome; D014162:Transfection; D014982:Xenopus laevis
chemical_list: D001381:Azepines; D006576:Heterocyclic Compounds, 4 or More Rings; D018722:Nicotinic Agonists; D011978:Receptors, Nicotinic; C403531:nicotinic receptor alpha4beta2; D008464:Mecamylamine; D009538:Nicotine; D003913:Dextroamphetamine; C475773:dianicline