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  • Title: Exploring the neuroleptic substituent in octoclothepin: potential ligands for positron emission tomography with subnanomolar affinity for α(1)-adrenoceptors.
    Author: Kristensen JL, Püschl A, Jensen M, Risgaard R, Christoffersen CT, Bang-Andersen B, Balle T.
    Journal: J Med Chem; 2010 Oct 14; 53(19):7021-34. PubMed ID: 20857909.
    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 D(2) and α(1)-adrenoceptor antagonists, with the aim of obtaining selective α(1)-adrenoceptor antagonists suitable for development as radioligands for imaging of central α(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 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 H(1) receptors, respectively.
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