Exploring the neuroleptic substituent in octoclothepin: potential ligands for positron emission tomography with subnanomolar affinity for alpha1-adrenoceptors

Jesper Langgaard Kristensen; Ask Pu¨schl; Martin Jensen; Rune Risgaard; Claus T Christoffersen; Benny Bang-Andersen; Thomas Balle

doi:10.1021/jm100652h

Exploring the neuroleptic substituent in octoclothepin: potential ligands for positron emission tomography with subnanomolar affinity for alpha₁-adrenoceptors

Jesper Langgaard Kristensen, Ask Pu¨schl, Martin Jensen, Rune Risgaard, Claus T Christoffersen, Benny Bang-Andersen, Thomas Balle

8 Citationer (Scopus)

Abstract

A series of 1-(10,11-dihydrodibenzo[b,f]thiepin-10-yl)-4-methylpiperazine analogues substituted in the 8-position of the 10,11-dihydrodibenzo[b,f]thiepine scaffold with aryl, heteroaryl, amine, and amide substituents are described. The compounds were designed using the previously reported Liljefors- Bøgesø pharmacophore model for dopamine D₂ and α₁-adrenoceptor antagonists, with the aim of obtaining selective α₁-adrenoceptor antagonists suitable for development as radioligands for imaging of central α₁-adrenoceptors by positron emission tomography. Sixteen aryl and heteroaryl substituted octoclothepin analogues were prepared by a convergent synthesis via coupling of 1-methyl-4-(8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-10, 11-dihydrodibenzo[b,f]thiepin-10-yl)piperazine with aryl and heteroaryl halides under palladium catalysis. The most selective compound obtained, (S)-N-((11-(4-methylpiperazin-1-yl)-10,11-dihydrodibenzo[b,f]thiepin-2-yl) methyl)isobutyramide (S)-35, showed a similar subnanomolar affinity compared to α_1a, α_1b, and α_1d- adrenoceptors and a selectivity ratio of 20, 440, and 20 with respect to D ₂, 5-HT_2C, and H₁ receptors, respectively.

Originalsprog	Engelsk
Tidsskrift	Journal of Medicinal Chemistry
Vol/bind	53
Udgave nummer	19
Sider (fra-til)	7021-7034
ISSN	0022-2623
DOI	https://doi.org/10.1021/jm100652h
Status	Udgivet - 14 okt. 2010

Emneord

Det tidligere Farmaceutiske Fakultet

Adgang til dokumentet

10.1021/jm100652h

Citationsformater

Exploring the neuroleptic substituent in octoclothepin : potential ligands for positron emission tomography with subnanomolar affinity for alpha₁-adrenoceptors. / Kristensen, Jesper Langgaard; Pu¨schl, Ask; Jensen, Martin et al.

I: Journal of Medicinal Chemistry, Bind 53, Nr. 19, 14.10.2010, s. 7021-7034.

Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › peer review

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abstract = "A series of 1-(10,11-dihydrodibenzo[b,f]thiepin-10-yl)-4-methylpiperazine analogues substituted in the 8-position of the 10,11-dihydrodibenzo[b,f]thiepine scaffold with aryl, heteroaryl, amine, and amide substituents are described. The compounds were designed using the previously reported Liljefors- B{\o}ges{\o} pharmacophore model for dopamine D2 and α1-adrenoceptor antagonists, with the aim of obtaining selective α1-adrenoceptor antagonists suitable for development as radioligands for imaging of central α1-adrenoceptors by positron emission tomography. Sixteen aryl and heteroaryl substituted octoclothepin analogues were prepared by a convergent synthesis via coupling of 1-methyl-4-(8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-10, 11-dihydrodibenzo[b,f]thiepin-10-yl)piperazine with aryl and heteroaryl halides under palladium catalysis. The most selective compound obtained, (S)-N-((11-(4-methylpiperazin-1-yl)-10,11-dihydrodibenzo[b,f]thiepin-2-yl) methyl)isobutyramide (S)-35, showed a similar subnanomolar affinity compared to α1a, α1b, and α1d- adrenoceptors and a selectivity ratio of 20, 440, and 20 with respect to D 2, 5-HT2C, and H1 receptors, respectively.",

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author = "Kristensen, {Jesper Langgaard} and Ask Pu¨schl and Martin Jensen and Rune Risgaard and Christoffersen, {Claus T} and Benny Bang-Andersen and Thomas Balle",

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AU - Kristensen, Jesper Langgaard

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AU - Jensen, Martin

AU - Risgaard, Rune

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AU - Bang-Andersen, Benny

AU - Balle, Thomas

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N2 - A series of 1-(10,11-dihydrodibenzo[b,f]thiepin-10-yl)-4-methylpiperazine analogues substituted in the 8-position of the 10,11-dihydrodibenzo[b,f]thiepine scaffold with aryl, heteroaryl, amine, and amide substituents are described. The compounds were designed using the previously reported Liljefors- Bøgesø pharmacophore model for dopamine D2 and α1-adrenoceptor antagonists, with the aim of obtaining selective α1-adrenoceptor antagonists suitable for development as radioligands for imaging of central α1-adrenoceptors by positron emission tomography. Sixteen aryl and heteroaryl substituted octoclothepin analogues were prepared by a convergent synthesis via coupling of 1-methyl-4-(8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-10, 11-dihydrodibenzo[b,f]thiepin-10-yl)piperazine with aryl and heteroaryl halides under palladium catalysis. The most selective compound obtained, (S)-N-((11-(4-methylpiperazin-1-yl)-10,11-dihydrodibenzo[b,f]thiepin-2-yl) methyl)isobutyramide (S)-35, showed a similar subnanomolar affinity compared to α1a, α1b, and α1d- adrenoceptors and a selectivity ratio of 20, 440, and 20 with respect to D 2, 5-HT2C, and H1 receptors, respectively.

AB - A series of 1-(10,11-dihydrodibenzo[b,f]thiepin-10-yl)-4-methylpiperazine analogues substituted in the 8-position of the 10,11-dihydrodibenzo[b,f]thiepine scaffold with aryl, heteroaryl, amine, and amide substituents are described. The compounds were designed using the previously reported Liljefors- Bøgesø pharmacophore model for dopamine D2 and α1-adrenoceptor antagonists, with the aim of obtaining selective α1-adrenoceptor antagonists suitable for development as radioligands for imaging of central α1-adrenoceptors by positron emission tomography. Sixteen aryl and heteroaryl substituted octoclothepin analogues were prepared by a convergent synthesis via coupling of 1-methyl-4-(8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-10, 11-dihydrodibenzo[b,f]thiepin-10-yl)piperazine with aryl and heteroaryl halides under palladium catalysis. The most selective compound obtained, (S)-N-((11-(4-methylpiperazin-1-yl)-10,11-dihydrodibenzo[b,f]thiepin-2-yl) methyl)isobutyramide (S)-35, showed a similar subnanomolar affinity compared to α1a, α1b, and α1d- adrenoceptors and a selectivity ratio of 20, 440, and 20 with respect to D 2, 5-HT2C, and H1 receptors, respectively.

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