Synthesis, nicotinic acetylcholine receptor binding, and pharmacological properties of 3′-(substituted phenyl)deschloroepibatidine analogs

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Abstract

A series of 3′-(substituted phenyl)deschloroepibatidine analogs (5aj) were synthesized. The α4β2 and α7 nicotinic acetylcholine receptor (nAChR) binding properties and functional activity in the tail-flick, hot-plate, locomotor, and body temperature tests in mice of 5aj were compared to those of the nAChR agonist, nicotine (1), epibatidine (4), and deschloroepibatidine (13), the partial agonist, varenicline (3), and the antagonist 2′-fluoro-3′-(substituted phenyl)deschloroepibatidine analogs (7aj). Unlike epibatidine and deschloroepibatidine, which are potent agonists in the tail-flick test, 5ak show no or very low antinociceptive activity in the tail-flick or hot-plate test. However, they are potent antagonists in nicotine-induced antinociception in the tail-flick test, but weaker than the corresponding 2′-fluoro-3′-(substituted phenyl)deschloroepibatidines.

Introduction

The use of tobacco products is believed to be in large part due to addiction to nicotine (1), which is one of the most abused reinforcing agents. It is estimated that there are four million smoking-related deaths annually from diseases such lung cancer, chronic obstructive pulmonary disease (COPD), and cardiovascular disease.1 Consequently, there is great interest in the development of pharmacotherapies for aiding people to stop smoking.2 Present FDA-approved drugs for treating smoking cessation include nicotine (1) replacement medication in the form of gum, patch, lozenge, sublingual tablet, nasal spray, and vapor inhaler, the antidepressant bupropion (2), and the α4β2 nAChR partial agonist varenicline (3).2, 3, 4

During the last few years, we have conducted structure–activity studies (SAR) using the potent nAChR agonist epibatidine (4) as a lead structure to identify pharmacophores for the nAChR. These studies have identified nAChR agonists as more potent than epibatidine as well as analogs that showed pure antagonist or partial agonist activity.5, 6, 7, 8, 9, 10, 11, 12 These studies showed that introduction of a substituted phenyl group at the 3′-position on the pyridine ring of epibatidine exerted a profound influence on both receptor binding (recognition) and receptor activation. Interestingly, substitution of different groups at the 2′-position distinguished between agonist and antagonist properties. In this study, we report the comparison of the nAChR binding and pharmacological properties of the 3′-(substituted phenyl)deschloroepibatidine analogs (5aj) to those of the nAChR agonist nicotine (1), epibatidine (4), and deschloroepibatidine (6), the partial agonist varenicline (3), and the corresponding 2′-fluoro-3′-(substituted phenyl)deschloroepibatidine analogs (7aj). The analogs 5aj showed α4β2 nAChR binding affinity as well as nAChR agonist and antagonist activity in mouse antinociceptive, hypothermia, and spontaneous activity test more like the partial agonist varenicline (3) than the nAChR agonist nicotine (1), epibatidine (4), and deschloroepibatidine (6a). Like the 2′-fluoro-3′-(substituted phenyl)deschloroepibatidine analogs 7aj, most of the 3-(substituted phenyl)deschloroepibatidine analogs 5aj were antagonist of nicotine-induced antinociception in the tail-flick test.

Section snippets

Chemistry

The synthesis of 5ah is shown in Scheme 1. Palladium acetate catalyzed coupling of tert-butoxycarbonyl-3′-bromodeschloroepibatidine (8)10 with the appropriately substituted phenylboronic acid in dimethoxyethane (DME) in the presence of tri-(o-tolyl)phosphine and sodium carbonate gave the tert-butoxycarbonyl-protected 3′-(substituted phenyl)deschloroepibatidine analogs (9ag). Reduction of the 4-nitrophenyl intermediate 9g with iron powder in hydrochloric acid gave the 4-aminophenyl compound 10

Biology

The Ki values for the inhibition of [3H]epibatidine binding at the α4β2 nAChR in male rat cerebral cortex for compounds 5aj are compared to values for nicotine (1), epibatidine (4), varenicline (3), and 2′-fluoro-3′-(substituted phenyl)deschloroepibatidine analogs (7aj) (Table 1). The binding assays were conducted and the Ki values calculated as previously described.8 Compounds (10 μM) were also evaluated for inhibition of binding to α7 nAChR using [125I] iodoMLA as previously reported.8

The

Results and discussion

The desired target compounds 5aj could be synthesized by a procedure similar to that used to prepare the previously reported 2′-fluoro-3′-(substituted phenyl)deschloroepibatidine analogs (7ak).11 The key step in both syntheses is palladium acetate catalyzed Suzuki17, 18 cross coupling of a 3-bromopyridine starting material 8 and 11 with the appropriately substituted phenylboronic acids.

Binding affinities for the 3′-(3- and 4-substituted phenyl)deschloroepibatidine analogs 5aj at α4β2 and α7

Experimental

Melting points were determined on a Mel-temp (Laboratory Devices Inc.) capillary tube apparatus. NMR spectra were recorded on a Bruker Avance 300 or AMX 500 Spectrometer using tetramethylsilane as internal standard. Thin layer chromatography was carried out on Whatman silica gel 60 plates. Visualization was accomplished under UV or in an iodine chamber. Microanalysis was carried out by Atlantic Microlab, Inc. Flash chromatography was carried out using silica gel 60 (230–400 mesh) using various

Acknowledgment

This research was supported by the National Institute on Drug Abuse, Grant DA12001.

References and notes (20)

  • M. Ezzati et al.

    Lancet

    (2003)
  • F.I. Carroll

    Bioorg. Med. Chem. Lett.

    (2004)
  • N. Miyaura et al.

    Tetrahedron Lett.

    (1979)
  • H. Rollema et al.

    Neuropharmacology

    (2007)
  • J.E. Henningfield et al.

    CA Cancer J. Clin.

    (2005)
  • G.M. Keating et al.

    CNS Drugs

    (2006)
  • R. Niaura et al.

    Nat. Rev. Drug Discov.

    (2006)
  • F.I. Carroll et al.

    J. Med. Chem.

    (2005)
  • F.I. Carroll et al.

    J. Med. Chem.

    (2001)
  • F.I. Carroll et al.

    J. Med. Chem.

    (2002)
There are more references available in the full text version of this article.

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