SSR591813, a Novel Selective and Partial α4β2 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 α₄β₂ nicotinic acetylcholine receptor (nAChR) subtypes (K_i = 107 and 36 nM, respectively) and displays selectivity for the α₄β₂ nAChR (K_i, human α₃β₄ > 1000, α₃β₂ = 116; α₁β₁δ_γ > 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.