Synthesis and Pharmacological Characterization of Enantiomerically Pure Muscarinic Agonists:  Difluoromuscarines

Angeli, Piero; Cantalamessa, Franco; Cavagna, R.; Conti, Paola; Amici, Marco De; Micheli, Carlo De; Gamba, A.; Marucci, Gabriella

doi:10.1021/jm960742w

Cited by 12 publications

(6 citation statements)

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“…Fluorine‐substituted analogs of naturally occurring and biologically active organic compounds are widely studied 1–18. It has already become a common practice in bioorganic chemistry to replace a hydroxyl group for a fluorine to generate a fluorinated enzyme substrate or inhibitor in a given enzymatic process 3–7.…”

Section: Introductionmentioning

confidence: 99%

When, in the context of drug design, can a fluorine atom successfully substitute a hydroxyl group?

Hoffmann

Rychlewski

2002

Int J of Quantum Chemistry

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ABSTRACT:In this article, we deal with the question of whether a fluorine atom can substitute a hydroxyl group in such a way that will lead to a compound showing a desired biologic activity, that is, a potential new drug. It is obvious that a fluorine atom differs from a hydroxyl group, as it cannot donate hydrogen bonds. However, it can accept them. Moreover, both fluorine and oxygen are of similar size and are the most electronegative elements. Therefore, a fluorine atom is thought to be a good substitute for a hydroxyl group. However, it was shown that for conformationally labile aliphatic compounds a replacement of a hydroxyl by a fluorine increases conformational diversity, so the fluorinecontaining aliphatic molecules are present in equilibrium at room temperature as a mixture of several different conformers. In contrast, for cyclic compounds the substitution of an OH group by an F atom does not much change shape and electrostatic potential around corresponding conformers. Moreover, these compounds are present in equilibrium at room temperature in aqueous solution as a mixture of the same most favored structures.

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Section: Introductionmentioning

confidence: 99%

When, in the context of drug design, can a fluorine atom successfully substitute a hydroxyl group?

Hoffmann

Rychlewski

2002

Int J of Quantum Chemistry

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“…Fluorine-substituted analogues of naturally occurring and biologically active organic compounds have become the focus of increasing interest. [1][2][3][4][5][6][7][8][9][11][12][13][14][15][16][17][18][19] They are thought to provide insight into the interactions with enzymatic binding sites. 1,2 Thus, it has already become a common practice in bioorganic chemistry to replace a hydroxyl group for a fluorine to generate a fluorinated enzyme substrate or inhibitor in a given enzymatic process.…”

Section: Introductionmentioning

confidence: 99%

“…Fluorinecontaining molecules. Structure, reactiVity, synthesis and applications; VCH Publishers: New York, 1988. groups of compounds were studied, 2, [15][16][17][18][19] carbohydrates seem to attract most of the attention. Among carbohydrates, there are a number of successful examples where substitution of a OH group by a F atom resulted in a compound which possessed biochemical and biological activity.…”

Section: Introductionmentioning

confidence: 99%

“…Fluorine-substituted analogues of naturally occurring and biologically active organic compounds have become the focus of increasing interest. − ,− They are thought to provide insight into the interactions with enzymatic binding sites. , Thus, it has already become a common practice in bioorganic chemistry to replace a hydroxyl group for a fluorine to generate a fluorinated enzyme substrate or inhibitor in a given enzymatic process. − The rationale for such a strategy stems from similarities between a F atom and a OH group, with particular reference to polarity as well as the close isosteric relationship between fluorine and oxygen. ,, Consequently, a F atom is considered to be a good substitute of a OH group because it introduces a small steric disturbance . Once introduced, the high carbon−fluorine bond energy 10 renders the substituent relatively resistant to metabolic transformation .…”

Section: Introductionmentioning

confidence: 99%

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Effects of Substituting a OH Group by a F Atom in d-Glucose. Ab Initio and DFT Analysis

Hoffmann

Rychlewski

2001

J. Am. Chem. Soc.

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High-level ab initio and DFT methods up to MP2/6-311++G//B3LYP/6-31G and B3LYP/6-311++G//B3LYP/6-31G levels have been used to assess the relative energies of 17 different structures of D-glucose and 13 different structures of 4-deoxy-4-fluoro-D-glucose. The structures were confirmed to correspond to minima on the potential energy surface at the RHF/6-31G level. Solvation Model 5.4/AM1 was used to calculate the effects of aqueous solution. The substitution of a OH group by a F atom does not much change the shape and electrostatic potential around corresponding conformers, but in the gas phase it destabilizes the cooperative network of intramolecular hydrogen bonds. This destabilization mostly affects structures with a chain of intramolecular hydrogen bonds oriented counterclockwise, as fluorine is unable to donate a hydrogen bond and therefore causes a gap in the chain. In contrast, for clockwise-oriented networks of hydrogen bonds, the fluorine can act as an acceptor at the end of a chain of cooperative hydrogen bonds. A slightly higher energy of anomeric and exo-anomeric stabilization is another effect of substituting the fourth hydroxyl group by a fluorine atom in D-glucose, observed both in the gas phase and in aqueous solution. For this reason, the alpha anomers contribute more to the equilibrium population of structures of 4-deoxy-4-fluoro-D-glucose than D-glucose. In aqueous solution, both D-glucose and its 4-deoxy-4-fluoro analogue are present as a mixture of mainly three corresponding structures. This indicates that 4-deoxy-4-fluoro-D-glucose is a good substitute for D-glucose in terms of its biochemical and biological activity. Moreover, this suggests that, for molecules with limited conformational freedom, the substitution of a OH group by a F atom is very likely to lead to a potential new drug. In contrast, it had already been shown that, for conformationally labile aliphatic compounds, replacement of a hydroxyl by a fluorine increases conformational diversity, so the fluorine-containing aliphatic molecules were not likely to be an example of a successful drug design. On the other hand, this work shows that, among molecules with limited conformational freedom, such as cyclic compounds, one is very likely to find targets for a successful rational drug design.

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“…Among the compounds related to muscarine (45a), four stereoisomers of difluormuscarine (45b) have been tested in vitro on guinea-pig tissues, and their muscarinic potency was evaluated at M2 (heart) and M3 (ileum and bladder) muscarinic receptor subtypes (see Table 8) [36]. The eutomer (+)-(2S,5S) 45b and distomer (-)-(2R,5R) 45b were also tested in vivo on pithed rat, and their muscarinic activity at the M1 receptor subtype was compared with those of racemic muscarine (45a) and (2S,3R,5S)-4-deoxy-4--fluormuscarine (45c).…”

Section: Spiro Compoundsmentioning

confidence: 99%

Muscarinic receptor agonists and antagonists

Zlotos¹,

Bender²,

Holzgrabe³

1999

Expert Opinion on Therapeutic Patents

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Although four different subtypes of the muscarinic acetylcholine (ACh) receptor with functional correlates are known to exist (function for M5 is still unclear), all muscarinic agonists and antagonists in clinical practice only show very weak selectivity. Therefore, intensive investigations are in progress to develop subtype selective ligands. This review describes the first M1 agonists and antagonists of the presynaptic M2 receptor, which can be used in the treatment of Alzheimer's disease (AD), and M3 antagonists, which will be useful in the treatment of urinary urge incontinence. In addition, muscarinic agonists were found to exhibit analgesic effects and M4 antagonists may be useful in the treatment of movement disorders. However, the latter two pharmacological findings will need more research work to become established in clinical trials.

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Synthesis and Pharmacological Characterization of Enantiomerically Pure Muscarinic Agonists: Difluoromuscarines

Cited by 12 publications

References 11 publications

When, in the context of drug design, can a fluorine atom successfully substitute a hydroxyl group?

When, in the context of drug design, can a fluorine atom successfully substitute a hydroxyl group?

Effects of Substituting a OH Group by a F Atom in d-Glucose. Ab Initio and DFT Analysis

Muscarinic receptor agonists and antagonists

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