Synthesis, Nicotinic Acetylcholine Binding, and in Vitro and in Vivo Pharmacological Properties of 2′-Fluoro-(carbamoylpyridinyl)deschloroepibatidine Analogues

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• 作者：Pauline W. Ondachi ; Ana H. Castro ; Charles W. Luetje ; Charles R. Wageman ; Michael J. Marks ; M. Imad Damaj ; S. Wayne Mascarella ; Hernán A. Navarro ; F. Ivy Carroll
• 刊名：ACS Chemical Neuroscience
• 出版年：2016
• 出版时间：July 20, 2016
• 年：2016
• 卷：7
• 期：7
• 页码：1004-1012
• 全文大小：341K
• 年卷期：0
• ISSN：1948-7193

文摘

In this study, we report the synthesis, nAChR in vitro and in vivo pharmacological properties of 2′-fluoro-(carbamoylpyridinyl)deschloroepibatidine analogues (5, 6a,b, and 7a,b), which are analogues of our lead structure epibatidine. All of the analogues had subnanomolar binding affinity for α4β2*-nAChRs, and all were potent antagonists of α4β2-nAChRs in an in vitro functional assay. Analogues 6a,b were also highly selective for α4β2- relative to α3β4- and α7-nAChRs. Surprisingly, all of the analogues were exceptionally potent antagonists of nicotine-induced antinociception in the mouse tail-flick test, relative to standard nAChR antagonists such as DHβE. 2′-Fluoro-(4-carbamoyl-3-pyridinyl)deschloroepitabidine (6a) displayed an attractive combination of properties, including subnanomolar binding affinity (K_i = 0.07 nM), submicromolar inhibition of α4β2-nAChRs in the functional assay (IC₅₀ = 0.46 μM) with a high degree of selectivity for α4β2- relative to the α3β4/α7-nAChRs (54-/348-fold, respectively), potent inhibition of [³H]dopamine release mediated by α4β2*- and α6β2*-nAChRs in a synaptosomal preparation (IC₅₀ = 21 and 32 nM, respectively), and an AD₅₀ of 0.007 μg/kg as an antagonist of nicotine induced antinociception in the mouse tail-flick test which is 64 250 times more potent than DHβE. These data suggest that compound 6a will be highly useful as a pharmacological tool for studying nAChRs and merits further development.