Diphenhydramine Derivatives: Through Manipulation toward Design

Harms, A. F.; Hespe, W.; Nauta, W. Th.; Rekker, R. F.; Timmerman, H.; Vries, J. de

doi:10.1016/b978-0-12-060306-0.50007-3

Cited by 24 publications

(20 citation statements)

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“…29–31 The features that have been systematically varied include the nature of the two required aromatic groups, the terminal basic amine and the aliphatic linker between these two features. 32,33 In this work, we examined similar structural variations using AMDA as the parent structure. These compounds closely resemble well-established H 1 antagonists: replacement of the ether oxygen of diphenhydramine by a methylene unit results in compound 6c and replacement of the pyridin-2-yl group of the H 1 antagonist pheniramine with a phenyl group results in 5c .…”

Section: Resultsmentioning

confidence: 99%

Synthesis, structure–affinity relationships, and modeling of AMDA analogs at 5-HT2A and H1 receptors: Structural factors contributing to selectivity

Shah

Mosier

Roth

et al. 2009

Bioorganic & Medicinal Chemistry

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Histamine H1 and serotonin 5-HT2A receptors present in the CNS have been implicated in various neuropsychiatric disorders. 9-Aminomethyl-9,10-dihydroanthracene (AMDA), a conformationally constrained diarylalkyl amine derivative, has affinity for both of these receptors. A structure-affinity relationship (SAFIR) study was carried out studying the effects of N-methylation, varying the linker chain length and constraint of the aromatic rings on the binding affinities of the compounds with the 5-HT2A and H1 receptors. Homology modeling of the 5-HT2A and H1 receptors suggests that AMDA and its analogs, the parent of which is a 5-HT2A antagonist, can bind in a fashion analogous to that of classical H1 antagonists whose ring systems are oriented towards the fifth and sixth transmembrane helices. The modeled orientation of the ligands are consistent with the reported site-directed mutagenesis data for 5-HT2A and H1 receptors and provide a potential explanation for the selectivity of ligands acting at both receptors.

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Section: Resultsmentioning

confidence: 99%

Synthesis, structure–affinity relationships, and modeling of AMDA analogs at 5-HT2A and H1 receptors: Structural factors contributing to selectivity

Shah

Mosier

Roth

et al. 2009

Bioorganic & Medicinal Chemistry

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“…Diethyl ether and pentane for column chromatography were distilled before use. 1 H and 13 C NMR spectra were recorded on a Varian Gemini 300 spectrometer (300 MHz and 75 MHz, respectively) and on a Varian Inova 400 spectrometer (400 MHz and 100 MHz, respectively). IR spectra were measured on a Perkin-Elmer PE 1760 FT instrument as KBr pellets or neat (in case of liquid compounds); absorptions are given in wave numbers (cm À1 ).…”

Section: Methodsmentioning

confidence: 99%

“…[1] For example, neobenodine and orphenandrine show anticholinergic as well as anthihistaminic properties. [2] Recently, diarylmethanols have been used in the synthesis of pharmaceuticals containing asymmetrical 1,1'-diarylalkyl subunits.…”

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confidence: 99%

Diarylmethanols by Catalyzed Asymmetric Aryl Transfer Reactions onto Aldehydes Using Boronic Acids as Aryl Source

2007

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Using a planar-chiral ferrocene as catalyst and combinations of functionalized aldehydes and substituted arylboronic acids as starting materials, asymmetric aryl transfer reactions give access to structurally diverse, optically active diarylmethanols in high yields and enantioselectivities.Keywords: arylboronic acids; C À C bond formation; diarylmethanols; enantioselective catalysis; organozinc reagents Diarylmethanols 3 with defined stereochemistry at the hydroxy-bearing carbon are important intermediates for the synthesis of numerous compounds with high biological and/or physiological activity.[1] For example, neobenodine and orphenandrine show anticholinergic as well as anthihistaminic properties.[2] Recently, diarylmethanols have been used in the synthesis of pharmaceuticals containing asymmetrical 1,1'-diarylalkyl subunits.[3] The most common routes towards diarylmethanols are either enantioselective reductions of prochiral benzophenone derivatives [4] or asymmetric carbon-carbon bond formations starting from aromatic aldehydes and appropriate organometallic compounds. [5,6] Despite the fact that the latter strategy has attracted considerable attention due to its enormous synthetic potential, the so far evaluated substrate range appears rather limited. Thus mostly, aryl transfer reactions onto (unsubstituted) benzaldehyde (Scheme 1, Ar 2 = Ph) or phenyl-to-aldehyde transfers have been studied leading to arylphenylmethanols. The synthesis of diarylmethanols with two differently substituted aryl groups via zinc reagents has, to the best of our knowledge, never been in the focus of an intensive study. [7] In 2002, we described a general approach for aryl transfer reactions to aromatic aldehydes involving arylzinc species formed in situ from arylboronic acids 1 and diethylzinc. Ferrrocene 4 served as catalyst (Scheme 1). [8] Noteworthy is the fact that with a single catalyst both enantiomers of 3 became accessible by choosing the appropriate combination of arylboronic acid 1 and aldehyde 2. Also in this case, only arylphenylmethanols were prepared.Wondering about the flexibility of this method and with the goal to investigate the applicability of the approach in the preparation of more functionalized molecules, we have now studied the catalytic synthesis of 1,1'-disubstituted diarylmethanols (e.g., products with aryls other than phenyl). This involved structural variations of both the arylboronic acids 1 as well as the aldehydes 2. The results are summarized in Table 1.To our delight we found that most diarylmethanols 3 were formed in good yields and high enantioselectivities (Figure 1). For example, 4-chlorophenyl-2'-methylphenylmethanol (3a) was obtained with 91 % ee in 71 % yield (Table 1, entry 1). In the catalysis starting from 2-bromobenzaldehyde (2c) and 3-methoxyphenylboronic acid (1c) diarylmethanol ent-3b was formed with 88 % ee in 66 % yield (entry 3). Using the "reverse combination" of substrates, the enantiomeric product 3b was obtained by aryl transfer from 2-bromophenylboronic acid (1b) ...

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“…A more promising starting point for the development of a quaternary radioligand appears to be in the series of compounds related to 4methyldiphenhydramine. The correlation between structure and Hl-antihistamine and antimuscarinic activity in this group has been studied in detail (Harms et al, 1975;Nauta & Rekker, 1978) and at least one quaternary derivative in this series, pirdonium, has an equal or higher affinity for the H1-receptor than its tertiary precursor, while retaining a good H1: muscarinic selectivity. A review of the properties of some of these compounds has led us to prepare and examine the properties of [3H]-( + )-N-methyl-4-methyldiphenhydramine ([3H] -QMDP) as a quaternary radioligand for the histamine H1-receptor.…”

Section: Introductionmentioning

confidence: 99%

[₃H]‐(+)‐N‐methyl‐4‐methyldiphenhydramine, a quaternary radioligand for the histamine H₁‐receptor

Treherne¹,

Young²

1988

British J Pharmacology

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Diphenhydramine Derivatives: Through Manipulation toward Design

Cited by 24 publications

References 58 publications

Synthesis, structure–affinity relationships, and modeling of AMDA analogs at 5-HT2A and H1 receptors: Structural factors contributing to selectivity

Synthesis, structure–affinity relationships, and modeling of AMDA analogs at 5-HT2A and H1 receptors: Structural factors contributing to selectivity

Diarylmethanols by Catalyzed Asymmetric Aryl Transfer Reactions onto Aldehydes Using Boronic Acids as Aryl Source

[₃H]‐(+)‐N‐methyl‐4‐methyldiphenhydramine, a quaternary radioligand for the histamine H₁‐receptor

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Diphenhydramine Derivatives: Through Manipulation toward Design

Cited by 24 publications

References 58 publications

Synthesis, structure–affinity relationships, and modeling of AMDA analogs at 5-HT2A and H1 receptors: Structural factors contributing to selectivity

Synthesis, structure–affinity relationships, and modeling of AMDA analogs at 5-HT2A and H1 receptors: Structural factors contributing to selectivity

Diarylmethanols by Catalyzed Asymmetric Aryl Transfer Reactions onto Aldehydes Using Boronic Acids as Aryl Source

[3H]‐(+)‐N‐methyl‐4‐methyldiphenhydramine, a quaternary radioligand for the histamine H1‐receptor

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[₃H]‐(+)‐N‐methyl‐4‐methyldiphenhydramine, a quaternary radioligand for the histamine H₁‐receptor