Exploring the neuroleptic substituent in octoclothepin: potential ligands for positron emission tomography with subnanomolar affinity for alpha1-adrenoceptors
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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; Risgaard, Rune; Christoffersen, Claus T; Bang-Andersen, Benny; Balle, Thomas.
In: Journal of Medicinal Chemistry, Vol. 53, No. 19, 2010, p. 7021-7034.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - Exploring the neuroleptic substituent in octoclothepin
T2 - potential ligands for positron emission tomography with subnanomolar affinity for alpha1-adrenoceptors
AU - Kristensen, Jesper Langgaard
AU - Pu¨schl, Ask
AU - Jensen, Martin
AU - Risgaard, Rune
AU - Christoffersen, Claus T
AU - Bang-Andersen, Benny
AU - Balle, Thomas
PY - 2010
Y1 - 2010
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 D(2) and a(1)-adrenoceptor antagonists, with the aim of obtaining selective a(1)-adrenoceptor antagonists suitable for development as radioligands for imaging of central a(1)-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 a(1a), a(1b), and a(1d)-adrenoceptors and a selectivity ratio of 20, 440, and 20 with respect to D(2), 5-HT(2C), and H(1) 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 D(2) and a(1)-adrenoceptor antagonists, with the aim of obtaining selective a(1)-adrenoceptor antagonists suitable for development as radioligands for imaging of central a(1)-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 a(1a), a(1b), and a(1d)-adrenoceptors and a selectivity ratio of 20, 440, and 20 with respect to D(2), 5-HT(2C), and H(1) receptors, respectively.
KW - Former Faculty of Pharmaceutical Sciences
U2 - 10.1021/jm100652h
DO - 10.1021/jm100652h
M3 - Journal article
C2 - 20857909
VL - 53
SP - 7021
EP - 7034
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
SN - 0022-2623
IS - 19
ER -
ID: 22431746