octoclothepine--(s)-isomer and octoclothepine

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.

Topics: Animals; Antipsychotic Agents; Binding, Competitive; Cattle; Cell Line; Cell Membrane Permeability; Cerebral Cortex; Cricetinae; Crystallography, X-Ray; Dibenzothiepins; Humans; Ligands; Models, Molecular; Piperazines; Positron-Emission Tomography; Radioligand Assay; Rats; Receptors, Adrenergic, alpha-1; Stereoisomerism; Structure-Activity Relationship

Octoclothepin (1) was resolved into its R and S enantiomers via the diastereomeric tartaric acid salts. The enantiomers were shown to be of high optical purity by 1H NMR with use of the chiral shift reagent (R)-(-)-2,2,2-trifluoro-1-(9-anthryl)ethanol. Pharmacological and biochemical testing confirmed that (S)-1 is the more potent dopamine (DA) D-2 antagonist both in vitro and in vivo, although the R enantiomer still has significant D-2 antagonistic activity. In contrast, both enantiomers were equally active in test models detecting activity at D-1 receptors, serotonin-2 (5-HT2) receptors and alpha 1 adrenoceptors. Contrary to a previous prediction, it was found that norepinephrine (NE) uptake inhibition was confined solely to the S enantiomer. Overall, (S)-1 has a "classical" neuroleptic profile, while the R enantiomer has a more "atypical" profile. These pharmacological profiles seem to be in agreement with the reported clinical profiles of the two enantiomers. A previous conformational study was revised in light of the biochemical test results with enantiomers of known optical purity. Their relative D-2 receptor affinity corresponded well with the calculated conformational energy difference between their "active conformations" deduced from a previously reported new D-2 receptor model. Also the high enantioselectivity of (S)-1 at the NE uptake site could be explained after a detailed conformational analysis showing strict requirements for the orientation of the piperazine lone-pair direction at the NE uptake site.

Topics: Animals; Antipsychotic Agents; Chemical Phenomena; Chemistry; Computer Simulation; Corpus Striatum; Dibenzothiepins; Dopamine Antagonists; Mice; Rats; Receptors, Dopamine D2; Stereoisomerism; Structure-Activity Relationship

Conformational analysis with molecular mechanics (MM2(85] and molecular superimposition studies of (1R,3S)-(+)- and (1S,3R)-(-)-4-[3-(4-fluorophenyl)-6-(trifluoromethyl)indan-1-yl]-1- piperazineethanol (tefludazine) and (S)-(+)- and (R)-(-)-octoclothepin have been employed to identify biologically active conformations of these compounds with respect to dopamine receptor antagonism and amine-uptake inhibition. In contrast to what is commonly assumed, these studies indicate that the conformation of (S)-(+)-octoclothepin responsible for the dopamine receptor antagonism is different from the one observed in the crystal. From least-squares molecular superimpositions with the potent and stereoselective dopamine receptor antagonist (1R,3S)-tefludazine, biologically active conformations for the two compounds on the dopamine receptor have been deduced. This analysis also rationalizes the enantioselectivity of octoclothepin on the dopamine receptor. The X-ray structure of (S)-(+)-octoclothepin is shown to correspond structurally to the 1S,3R enantiomer of tefludazine, which is an amine-uptake inhibitor. This correspondence provides a structural basis for the norepinephrine (NE) uptake blocking properties of octoclothepin. It is predicted that the enantioselectivity of the NE-uptake inhibition of octoclothepin should be low with the S-(+) enantiomer as the more active optical isomer. A comparison of the deduced biologically active conformation of (S)-(+)-octoclothepin with (+)-dexclamol is also discussed on the basis of earlier derived superimposition studies with (+)-dexclamol.

Topics: Antipsychotic Agents; Dibenzocycloheptenes; Dibenzothiepins; Dopamine; Molecular Conformation; Neurotransmitter Uptake Inhibitors; Norepinephrine; Piperazines; Receptors, Dopamine; Stereoisomerism; Structure-Activity Relationship