• Journal Article

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

Citation

Ondachi, P. W., Castro, A. H., Luetje, C. W., Wageman, C. R., Marks, M. J., Damaj, M. I., ... Carroll, F. I. (2016). Synthesis, Nicotinic Acetylcholine Binding, and in Vitro and in Vivo Pharmacological Properties of 2 '-Fluoro-(carbamoylpyridinyl)deschloroepibatidine Analogues. ACS Chemical Neuroscience, 7(7), 1004-1012. DOI: 10.1021/acschemneuro.6b00107, 10.1021/acschemneuro.6b00107

Abstract

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 alpha 4 beta 2*-nAChRs, and all were potent antagonists of alpha 4 beta 2-nAChRs in an in vitro functional assay. Analogues 6a,b were also highly selective for alpha 4 beta 2- relative to alpha 3 beta 4- and alpha 7-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 DH beta E. 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 alpha 4 beta 2-nAChRs in the functional assay (IC50 = 0.46 mu M) with a high degree of selectivity for alpha 4 beta 2-relative to the alpha 3 beta 4/alpha 7-nAChRs (54-/348-fold, respectively), potent inhibition of [H-3]dopamine release mediated by alpha 4 beta 2*-and alpha 6 beta 2*-nAChRs in a synaptosomal preparation (IC50 = 21 and 32 nM, respectively), and an AD(50) of 0.007 mu g/kg as an antagonist of nicotine induced antinociception in the mouse tail -flick test which is 64 250 times more potent than DH beta E. These data suggest that compound 6a will be highly useful as a pharmacological tool for studying nAChRs and merits further development.