Nitrogen substitution modifies the activity of cytisine on neuronal nicotinic receptor subtypes

Carbonnelle, Eric; Sparatore, Fabio; Canu-Boido, Caterina; Salvagno, Cristian; Baldani-Guerra, Barbara; Terstappen, Georg C.; Zwart, Ruud; Vijverberg, Henk P.M.; Clementi, Francesco; Gotti, Cecilia

doi:10.1016/s0014-2999(03)01817-x

Cited by 54 publications

(57 citation statements)

References 39 publications

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“…As discussed above, varenicline displays similar potency and efficacy values at both rat and human ␣4␤2 receptors (Table 1) (Coe et al, 2005a). In addition, cytisine displays similar potencies and efficacies on both rat and human ␣4␤2, ␣3␤4, and ␣7 receptors (ChavezNoriega et al, 1997;Papke and Porter Papke, 2002;Carbonnelle et al, 2003). Thus, the actions of varenicline on rat neuronal nAChRs that we describe here are likely to be relevant to the actions of varenicline on human receptors.…”

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confidence: 54%

“…More interesting is the variation in efficacy, which ranges from low (Ͻ15% for ␣4␤2, ␣3␤2, and ␣6-containing receptors), to high (93% and 75% for ␣7 and ␣3␤4 receptors, respectively). This variation in efficacy is not surprising considering that the initial inspiration for the development of varenicline was cytisine (Coe et al, 2005a), an agonist that displays low efficacy at ␣4␤2 receptors and high efficacy at ␣3␤4 and ␣7 receptors (Luetje and Patrick, 1991;Papke and Heinemann, 1994;Chavez-Noriega et al, 1997Stauderman et al, 1998;Papke and Porter Papke, 2002;Carbonnelle et al, 2003;Slater et al, 2003). Compared with cytisine, varenicline has a similarly low efficacy at ␣4␤2 and other ␤2-containing receptors and a similarly high efficacy at ␣3␤4 and ␣7 receptors.…”

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confidence: 99%

“…In equilibrium binding assays, cytisine is selective for the ␣4␤2 subunit combination, compared with other important nAChR subtypes such as ␣3␤4 and ␣7 (Parker et al, 1998;Stauderman et al, 1998;Chavez-Noriega et al, 2000;Carbonnelle et al, 2003;Slater et al, 2003;Xiao et al, 2004). In functional assays, cytisine shows greater potency at ␣4␤2 receptors than at many other subunit combinations.…”

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confidence: 99%

“…Cytisine also displays a wide variation in efficacy at various subunit combinations. Although cytisine is a high-efficacy agonist at ␣7 receptors and at various ␤4-containing receptors, such as ␣3␤4, cytisine is a low-efficacy partial agonist at ␣4␤2 and other ␤2 containing receptors (Luetje and Patrick, 1991;Papke and Heinemann, 1994;Chavez-Noriega et al, 1997;Stauderman et al, 1998;Chavez-Noriega et al, 2000;Papke and Porter Papke, 2002;Carbonnelle et al, 2003;Slater et al, 2003 example, bromination or iodination of the 3-position in the pyridone ring of cytisine preserves the full efficacy at ␣7 receptors and increases the efficacy at ␣4␤2 receptors (Slater et al, 2003), whereas the addition of side groups at the basic nitrogen of cytisine can reduce or eliminate efficacy for various receptors (Carbonnelle et al, 2003).…”

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confidence: 99%

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Varenicline Is a Partial Agonist at α4β2 and a Full Agonist at α7 Neuronal Nicotinic Receptors

Mihalak¹,

Carroll²,

Luetje³

2006

Mol Pharmacol

524

465

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Varenicline, a new nicotinic ligand based on the structure of cytisine, has recently been approved by the U.S. Food and Drug Administration for use as a smoking cessation aid. Varenicline has been shown to be a partial agonist of ␣4␤2 receptors, and in equilibrium binding assays, it is highly selective for the ␣4␤2 receptor. In this study, we have examined the functional activity of varenicline at a variety of rat neuronal nicotinic receptors expressed in Xenopus laevis oocytes and assayed under two-electrode voltage clamp. We also find that varenicline is a potent, partial agonist at ␣4␤2 receptors, with an EC 50 of 2.3 Ϯ 0.3 M and an efficacy (relative to acetylcholine) of 13.4 Ϯ 0.4%. Varenicline has lower potency and higher efficacy at ␣3␤4 receptors, with an EC 50 of 55 Ϯ 8 M and an efficacy of 75 Ϯ 6%. Varenicline also seems to be a weak partial agonist at ␣3␤2 and ␣6-containing receptors, with an efficacy Ͻ10%. It is remarkable that varenicline is a potent, full agonist at ␣7 receptors with an EC 50 of 18 Ϯ 6 M and an efficacy of 93 Ϯ 7% (relative to acetylcholine). Thus, whereas varenicline is a partial agonist at some heteromeric neuronal nicotinic receptors, it is a full agonist at the homomeric ␣7 receptor. Some combination of these actions may be involved in the mechanism of varenicline as a smoking cessation aid.

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confidence: 54%

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confidence: 99%

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confidence: 99%

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Varenicline Is a Partial Agonist at α4β2 and a Full Agonist at α7 Neuronal Nicotinic Receptors

Mihalak¹,

Carroll²,

Luetje³

2006

Mol Pharmacol

524

465

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“…Nicotinic receptors form a family of acetylcholine (Ach)-gated cation channels made up of different subtypes, localized in the central and peripheral nervous systems [5,6]. Nicotine, a naturally occurring alkaloid, affects the functioning of peripheral nervous system.…”

Section: Introductionmentioning

confidence: 99%

Experimental studies of charge density distribution in the crystals of cytisine and N-methylcytisine. Inside the Fake Tobacco

2017

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The high-resolution X-ray data for two bioactive molecules: cytisine (1) and its N-methyl derivative (2) have been collected up to sinθ/λ = 1.12 Å −1 for 1 and 1.0 Å −1 for 2. This data was used for modeling of the fine features of electron density distribution, including bonding density and electron lone pairs. The quality of the model was checked by, e.g., rigid bond test and RDA analysis. The topological analysis (gradient field analysis) has been also performed for both inter-and intramolecular interactions. In case of 1 a number of intermolecular interactions, from relatively strong N-H···O hydrogen bonds to weak H···H contacts was found, and their topological features were analyzed. For N-methyl derivative, only few intermolecular bonding contacts were found. The analyzed features show that besides the structural similarities of both alkaloids, the electron density distribution and consequently all its derivatives differ quite significantly in places.

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Cholinergics/Anticholinergics/Muscarinics/Nicotinics

Griffith

2010

Burger's Medicinal Chemistry and Drug Discovery

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This chapter quickly summarizes the cholinergic nervous system and the structures of muscarinic and nicotinic receptors. The structure–activity relationships of muscarinic agonists and antagonists are discussed with reference to attempts to develop of drugs selective for one of the five muscarinic receptors, both agonist and antagonists. The structure–activity relationships of agonists and antagonists of nicotinic receptors are presented with initial concentration on the neuronal nicotinic receptors and ending with neuromuscular blockers used in surgery.

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Nitrogen substitution modifies the activity of cytisine on neuronal nicotinic receptor subtypes

Cited by 54 publications

References 39 publications

Varenicline Is a Partial Agonist at α4β2 and a Full Agonist at α7 Neuronal Nicotinic Receptors

Varenicline Is a Partial Agonist at α4β2 and a Full Agonist at α7 Neuronal Nicotinic Receptors

Experimental studies of charge density distribution in the crystals of cytisine and N-methylcytisine. Inside the Fake Tobacco

Cholinergics/Anticholinergics/Muscarinics/Nicotinics

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