Exploring the neuroleptic substituent in octoclothepin: potential ligands for positron emission tomography with subnanomolar affinity for alpha(1)-adrenoceptors.

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Kristensen JL, Puschl A, Jensen M, Risgaard R, Christoffersen CT, Bang-Andersen B, Balle T

Exploring the neuroleptic substituent in octoclothepin: potential ligands for positron emission tomography with subnanomolar affinity for alpha(1)-adrenoceptors.

J Med Chem. 2010 Oct 14;53(19):7021-34. doi: 10.1021/jm100652h.

PubMed ID

20857909 [ View in PubMed

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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-Bogeso pharmacophore model for dopamine D(2) and alpha(1)-adrenoceptor antagonists, with the aim of obtaining selective alpha(1)-adrenoceptor antagonists suitable for development as radioligands for imaging of central alpha(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 alpha(1a), alpha(1b), and alpha(1d)-adrenoceptors and a selectivity ratio of 20, 440, and 20 with respect to D(2), 5-HT(2C), and H(1) receptors, respectively.

DrugBank Data that Cites this Article

Binding Properties

Drug	Target	Property	Measurement	pH	Temperature (°C)
Sertindole	5-hydroxytryptamine receptor 2C	Ki (nM)	0.2	N/A	N/A	Details
Sertindole	Dopamine D2 receptor	Ki (nM)	0.45	N/A	N/A	Details