Quaternary Carbon Compounds. I. Trialkylacetic Acids as Antispasmodic Agents<sup>1</sup>

A novel class of isochroman dopamine analogues, 1, originally reported by Abbott Laboratories, had greater than 100-fold selectivity for D1-like vs. D2-like receptors. We synthesized a parallel series of chroman compounds, 2, and showed that repositioning the oxygen in the heterocyclic ring reduced potency and conferred D2-like receptor selectivity to these compounds. In silico modeling supported the hypothesis that the altered pharmacology for 2 was due to potential intramolecular hydrogen bonding between the oxygen in the chroman ring and the meta-hydroxyl of the catechol moiety. This interaction realigns the catechol hydroxyl groups and disrupts key interactions between these ligands and critical serine residues in TM5 of the D1-like receptors. This hypothesis was tested by the synthesis and pharmacological evaluation of a parallel series of carbocyclic compounds, 3. Our results suggest that when the potential for intramolecular hydrogen bonding is removed, D1-like receptor potency and selectivity is restored.

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“…Katsuri and colleagues have described the difficulties in hydrolyzing sterically crowded nitriles in both acidic and basic conditions. [40, 41] …”

Section: Resultsmentioning

confidence: 99%

Mapping the Catechol Binding Site in Dopamine D₁Receptors: Synthesis and Evaluation of Two Parallel Series of Bicyclic Dopamine Analogues

et al. 2011

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“…6‐cyano‐6‐methylundecane : The synthesis was adapted from previous literature 26. A mixture of 1propionitrile (10.5 g, 0.19 mol), 1bromopentane (66.5 g, 0.44 mol), and sodium‐dried toluene (70 mL, SDS) was placed in a 500 mL flask fitted with a condenser and a 500 mL dropping funnel.…”

Section: Methodsmentioning

confidence: 99%

N,N′‐Disubstituted Ureas: Influence of Substituents on the Formation of Supramolecular Polymers

Lortie¹,

Boileau²,

Bouteiller³

2003

Chemistry A European J

109

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Symmetrical N,N'-disubstituted ureas have been synthesized and characterized. Among them, the branched dialkylureas prepared are highly soluble in organic media. Moreover, the solutions obtained are very viscous in heptane, if the branched alkyl groups are not too bulky (i.e. a methyl group on the alpha carbon, or an ethyl group on the beta carbon). Due to the strong, bifurcated hydrogen bonds between the urea moieties, linear supramolecular polymers are formed. The degree of association of these supramolecular polymers has been determined by FTIR spectroscopy.

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“…Determination of ethereal sulphate. The turbidimetric method of Sperber (1948), with a standard curve of 0.05-0-8mg. of 0s3/10ml., was used.…”

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confidence: 99%

Studies on flavonoid metabolism. Metabolism of (+)-catechin in the guinea pig

Das

Griffiths

1968

Biochemical Journal

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1. Administration of (+)-catechin to the guinea pig gives rise to a number of phenolic acids and lactones, which have been identified by chromatographic and spectrophotometric methods. The major phenolic acid metabolite is m-hydroxybenzoic acid and the major lactone metabolite is delta-(3-hydroxyphenyl)-gamma-valerolactone. 2. The phenolic acid and lactone metabolites are excreted in both free and conjugated forms, including their glucuronides and to a lesser degree their ethereal sulphates. 3. Administration of certain of the metabolites isolated has permitted certain sequential relationships of these intermediates to be established. 4. Degradation of (+)-catechin in the guinea pig is effected at least in part by the gut microflora and is suppressed by aureomycin plus phthaloyl-sulphathiazole.

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Quaternary Carbon Compounds. I. Trialkylacetic Acids as Antispasmodic Agents¹

Cited by 53 publications

References 0 publications

Mapping the Catechol Binding Site in Dopamine D₁Receptors: Synthesis and Evaluation of Two Parallel Series of Bicyclic Dopamine Analogues

Mapping the Catechol Binding Site in Dopamine D₁Receptors: Synthesis and Evaluation of Two Parallel Series of Bicyclic Dopamine Analogues

N,N′‐Disubstituted Ureas: Influence of Substituents on the Formation of Supramolecular Polymers

Studies on flavonoid metabolism. Metabolism of (+)-catechin in the guinea pig

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Quaternary Carbon Compounds. I. Trialkylacetic Acids as Antispasmodic Agents1

Cited by 53 publications

References 0 publications

Mapping the Catechol Binding Site in Dopamine D1Receptors: Synthesis and Evaluation of Two Parallel Series of Bicyclic Dopamine Analogues

Mapping the Catechol Binding Site in Dopamine D1Receptors: Synthesis and Evaluation of Two Parallel Series of Bicyclic Dopamine Analogues

N,N′‐Disubstituted Ureas: Influence of Substituents on the Formation of Supramolecular Polymers

Studies on flavonoid metabolism. Metabolism of (+)-catechin in the guinea pig

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Product

Resources

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Quaternary Carbon Compounds. I. Trialkylacetic Acids as Antispasmodic Agents¹

Mapping the Catechol Binding Site in Dopamine D₁Receptors: Synthesis and Evaluation of Two Parallel Series of Bicyclic Dopamine Analogues

Mapping the Catechol Binding Site in Dopamine D₁Receptors: Synthesis and Evaluation of Two Parallel Series of Bicyclic Dopamine Analogues