title: Exploring the neuroleptic substituent in octoclothepin: potential ligands for positron emission tomography with subnanomolar affinity for α(1)-adrenoceptors.
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.
authors.affiliation: Department of Medicinal Chemistry, The Faculty of Pharmaceutical Sciences, University of Copenhagen, Universitetsparken 2, 2100 Copenhagen, Denmark.
authors.forename: Jesper L
authors.initials: JL
authors.lastname: Kristensen
authors.forename: Ask
authors.initials: A
authors.lastname: Püschl
authors.forename: Martin
authors.initials: M
authors.lastname: Jensen
authors.forename: Rune
authors.initials: R
authors.lastname: Risgaard
authors.forename: Claus T
authors.initials: CT
authors.lastname: Christoffersen
authors.forename: Benny
authors.initials: B
authors.lastname: Bang-Andersen
authors.forename: Thomas
authors.initials: T
authors.lastname: Balle
mesh_terms: D000818:Animals; D014150:Antipsychotic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001667:Binding, Competitive; D002417:Cattle; D002460:Cell Line; D002463:Cell Membrane Permeability; D002540:Cerebral Cortex / Q000378:metabolism; D006224:Cricetinae; D018360:Crystallography, X-Ray; D003988:Dibenzothiepins / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D010879:Piperazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D049268:Positron-Emission Tomography; D011869:Radioligand Assay; D051381:Rats; D018340:Receptors, Adrenergic, alpha-1 / Q000378:metabolism*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D014150:Antipsychotic Agents; D003988:Dibenzothiepins; D008024:Ligands; C553285:N-((11-(4-methylpiperazin-1-yl)-10,11-dihydrodibenzo(b,f)thiepin-2-yl)methyl)isobutyramide; D010879:Piperazines; D018340:Receptors, Adrenergic, alpha-1; C100288:octoclothepine