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. 2015 Sep 1;23(17):5693-701.
doi: 10.1016/j.bmc.2015.07.021. Epub 2015 Jul 17.

Synthesis, Nicotinic Acetylcholine Receptor Binding, in Vitro and in Vivo Pharmacology Properties of 3'-(substituted Pyridinyl)-Deschloroepibatidine Analogs

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Synthesis, Nicotinic Acetylcholine Receptor Binding, in Vitro and in Vivo Pharmacology Properties of 3'-(substituted Pyridinyl)-Deschloroepibatidine Analogs

Pauline W Ondachi et al. Bioorg Med Chem. .
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Abstract

Over the last several years we have synthesized and studied the in vitro and in vivo nAChR pharmacological properties of epibatidine (4) analogs. In this study we report the synthesis, nAChR in vitro and in vivo pharmacological properties of 3'-(substituted pyridinyl)-deschloroepibatidine analogs (5a-e and 6a-e). All of the analogs had high binding affinity for α4β2(∗)-nAChRs. Several of the analogs were potent antagonists of α4β2-nAChRs in in vitro efficacy tests and were potent antagonists of nicotine-induced antinociception in the mouse tail-flick test. Compound 6b had a Ki = 0.13 nM in the binding assay, 25- and 46-fold selectivity for the α4β2(∗)-nAChR relative to the α3β4- and α7-nAChR, respectively, in the in vitro efficacy test and an AD50 = 0.13 μg/kg in the tail-flick test. Combined with favorable calculated physiochemical properties compared to varenicline, our findings suggest that 6b should be considered for development as a potential pharmacotherapy for treating nicotine addiction and other CNS disorders.

Keywords: Epibatidine analogs; In vitro/in vivo study; Nicotine receptor; Varenicline; nAChR antagonist.

Figures

Scheme 1
Scheme 1
Reagents and conditions: (a) 4-Pyridine boronic ester, Pd(PPh3)4, K2CO3, DME, H2O, 100 °C, 24 h (for 5a); (b) 2-fluoropyridine-4-boronic acid (for 5b) or 2-Chloropyridine-4-boronic acid (for 5c), Pd(OAc)2, P(o-tolyl)3, Na2CO3, DME, H2O, 80 °C, 5 h; (c) TFA, CH2Cl2, rt, 3 h; (d) Bis(pinacolato)diboron, KOAc, PdCl2(dppf), 1,4-dioxane, 110 °C, 18 h; (e) 3-amino-4-bromopyridine (for 8d), 4-bromo-2-methoxypyridine (for 8e), Pd(PPh3)4, K2CO3, 1,4-dioxane, H2O, 110 °C, overnight.
Scheme 2
Scheme 2
Reagents and conditions: (a) 2-Fluoro-5-boronic acid (for 10b) or 2-Chloro-5-boronic acid (for 10c), Pd(OAc)2, P(o-tolyl)3, Na2CO3, DME, H2O, 80 °C, 5 h; (b) Pyridine-3-boronic acid (for 10a), or 2-methoxypyridine-5-boronic acid (for 10e), or 2-aminopyridine-5-boronic (for 10d), Pd(PPh3)4, K2CO3, dioxane, H2O, reflux, 24 h; (c) TFA, CH2Cl2, rt, 2 h.
Chart 1
Chart 1
Structures of Compounds 1–4, 5a–e and 6a–e.

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