Syntheses and evaluation of halogenated cytisine derivatives and of bioisosteric thiocytisine as potent and selective nAChR ligands

Imming, Peter; Klaperski, Paul; Stubbs, Milton T.; Seitz, G.; Gündisch, Daniela

doi:10.1016/s0223-5234(01)01222-3

Cited by 82 publications

(41 citation statements)

References 46 publications

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“…Compounds were derived as described previously (Imming et al, 2001;Fitch et al, 2005). In brief, cytisine was obtained by isolation from seeds and pods from Laburnum anagyroides and Laburnum watereri and was subsequently protected at the secondary nitrogen with N-tBoc-anhydride.…”

Section: Synthesismentioning

confidence: 99%

Cytisine-Based Nicotinic Partial Agonists as Novel Antidepressant Compounds

Mineur

Eibl²,

Kochevar³

et al. 2009

J Pharmacol Exp Ther

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Nicotine and other nicotinic agents are thought to regulate mood in human subjects and have antidepressant-like properties in animal models. Recent studies have demonstrated that blockade of nicotinic acetylcholine receptors (nAChRs) including those containing the ␤2 subunit (␤2*), results in antidepressant-like effects. Previous studies have shown that cytisine, a partial agonist at ␣4/␤2* nAChRs, and a full agonist at ␣3/␤4* and ␣7 nAChRs, has antidepressant-like properties in several rodent models of antidepressant efficacy; however, it is not clear whether more selective partial agonists will also be effective in these models. We tested cytisine and two derivatives, 5-bromo-cytisine (5-Br-Cyt) and 3-(pyridin-3Ј-yl)-cytisine (3-pyr-Cyt) for their ability to act as a partial agonist of different nAChR subtypes and to show antidepressant-like activity in C57/BL6 mice in the tail suspension, the forced-swim, and the novelty-suppressed feeding tests. 3-pyr-Cyt was a partial agonist with very low efficacy at ␣4/␤2* nAChRS but had no agonist effects at other nAChRs normally targeted by cytisine, and it was effective in mouse models of antidepressant efficacy. Animals showed dose-dependent antidepressant-like effects in all three behavioral paradigms. 5-Br-Cyt was not effective in behavioral tests when administered peripherally, probably because of its inability to penetrate the blood-brain barrier, because it efficiently reduced immobility in the tail suspension test when administered intraventricularly. These results suggest that novel nicotinic partial agonists may provide new possibilities for development of drugs to treat mood disorders.

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Section: Synthesismentioning

confidence: 99%

Cytisine-Based Nicotinic Partial Agonists as Novel Antidepressant Compounds

Mineur

Eibl²,

Kochevar³

et al. 2009

J Pharmacol Exp Ther

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“…Unlike the situation for nicotine versus nornicotine (Fig. 4), the presence of a methyl group in caulophylline does not increase but instead markedly reduces affinity compared to cytisine (Imming et al, 2001). Further N-methylation to provide a quaternary amine largely restored affinity for the α 4 β 2 receptor.…”

Section: Cytisine-based Nicotinic Agonistsmentioning

confidence: 78%

Nicotinic Agonists, Antagonists, and Modulators From Natural Sources

2005

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1. Acetylcholine receptors were initially defined as nicotinic or muscarinic, based on selective activation by two natural products, nicotine and muscarine. Several further nicotinic agonists have been discovered from natural sources, including cytisine, anatoxin, ferruginine, anabaseine, epibatidine, and epiquinamide. These have provided lead structures for the design of a wide range of synthetic agents. 2. Natural sources have also provided competitive nicotinic antagonists, such as the Erythrina alkaloids, the tubocurarines, and methyllycaconitine. Noncompetitive antagonists, such as the histrionicotoxins, various izidines, decahydroquinolines, spiropyrrolizidine oximes, pseudophrynamines, ibogaine, strychnine, cocaine, and sparteine have come from natural sources. Finally, galanthamine, codeine, and ivermectin represent positive modulators of nicotinic function, derived from natural sources. 3. Clearly, research on acetylcholine receptors and functions has been dependent on key natural products and the synthetic agents that they inspired.

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“…One of the reasons for, or maybe a consequence of, the difficulties in studying nAChR subtypes is the lack of selective ligands: as our knowledge in this field increases, the definition of the selectivity changes. Cytisine, for instance, is considered selective for the a4b2 receptor, 54 and, in fact, it binds to this subtype with an affinity 2000-fold higher than to the a7 subtype; 55 however, it was shown that its selectivity toward other heteromeric receptors is lower, the affinity ratios between a4b2 and a2b2, a2b4, a3b2, a3b4 and a4b4 being 0.4, 5, 14, 56, and 1, respectively. 56 Another example may be 3-[2-(S)-azetidinylmethoxy]pyridine (A-85380), which was reported to be a a4b2 selective ligand (K i 0.017 nM), 57,58 but it has been recently shown that it displaces [ 125 I]conotoxin MII from its binding sites with an IC 50 0.091 nM, indicating that it interacts with high affinity also to a6b2* and a3b2* receptors.…”

Section: S T R U C T U R Ementioning

confidence: 99%

“…Compared to cytisine, the affinity for the a4b2 subtype is 6 to 12 times higher, but selectivity is one order of magnitude lower. 55 The halogenation in position 5, or the double substitution in positions 3 and 5, gives compounds (64 and 65, respectively) with affinity similar to cytisine (K i 0.23-10.8 nM), but with lower selectivity. The functional activity of the brominated derivatives 63a, 64a, and 65a was tested on recombinant receptors expressed in Xenopus oocytes (whole-cell current recording): 63a, as well as cytisine, proved to be a full agonist at a7 and partial agonist at the a4b2 and a4b4 subtypes, while 64a and 65a were partial agonists at the a7 and a4b4 subtypes, but did not activate the a4b2, on which 65a was actually an antagonist.…”

Section: Rigid Compoundsmentioning

confidence: 99%

“…103 The replacement of the oxygen with sulphur led to thiocytisine 66, which was shown to bind with subnanomolar affinity at the a4b2 subtype, with improved selectivity over the lead compound (K i (a4b2)/K i (a7) 4800). 55 Compounds 67 and 68 were designed as rigid analogues derived by hybridization between the arecoline derivatives arecolone and isoarecolone 104 and the cyclopentanone derivative AG4. 105 Despite the high structural similarity between these molecules, only compound 68b interacts with the nAChR with an affinity (K i 4.2 mM on rat cerebral cortex) 6-fold higher than AG4, but two orders of magnitude lower than arecolone and isoarecolone.…”

Section: Rigid Compoundsmentioning

confidence: 99%

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Cholinergic nicotinic receptors: Competitive ligands, allosteric modulators, and their potential applications

Romanelli

Gualtieri

2003

Medicinal Research Reviews

111

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Discovery of the important role played by nicotinic acetylcholine receptors (nAChRs) in several CNS disorders has called attention to these membrane proteins and to ligands able to modulate their functions. The existence of different subtypes at multiple levels has complicated the understanding of this receptor's physiological role, but at the same time has increased the efforts to discover selective compounds in order to improve the pharmacological characterization of this kind of receptor and to make the possible therapeutical use of its modulators safer. This review focuses on the structure of new ligands for nAChRs, agonists, antagonists and allosteric modulators, and on their possible applications.

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Syntheses and evaluation of halogenated cytisine derivatives and of bioisosteric thiocytisine as potent and selective nAChR ligands

Cited by 82 publications

References 46 publications

Cytisine-Based Nicotinic Partial Agonists as Novel Antidepressant Compounds

Cytisine-Based Nicotinic Partial Agonists as Novel Antidepressant Compounds

Nicotinic Agonists, Antagonists, and Modulators From Natural Sources

Cholinergic nicotinic receptors: Competitive ligands, allosteric modulators, and their potential applications

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