Serotonin Transporter Ligands - CoMFA and CoMSIA Studies for the Prediction of New Radiotracers

Veränderungen im serotonergen System können über eine Visualisierung des Serotonintransporters (SERT) mittels Positronen-Emissions-Tomographie (PET) nachvollzogen werden. Bisher fehlt es jedoch an geeigneten PET-Tracern für den SERT. Das Ziel der vorliegenden Arbeit war eine quantitative Untersuchung der Struktur-Wirkungsbeziehungen (QSAR) von SERT-Liganden. Dabei sollte eine klare Abgrenzung zwischen Struktur-Wirkungsbeziehungen am SERT und am strukturell ähnlichen Noradrenalintransporter (NET) erzielt werden. Im Anschluss stand das Design neuer potentieller PET-Tracer für den SERT unter Berücksichtigung der Möglichkeit zur F18-Markierung. Es wurde mit einem heterogenen Datensatz bestehend aus 19 selektiven und nicht-selektiven SERT-Liganden gearbeitet, für die Bindungsdaten sowohl für den SERT als auch für den NET vorlagen. Grundvoraussetzung einer 3D QSAR Studie ist ein geeignetes Alignment der Substanzen. Dieses basierte für die vorliegende Arbeit auf einem Pharmakophormodell aus der Literatur. Zur Überlagerung der Substanzen wurde GASP herangezogen. Für die 3D QSAR Studien wurde neben der etablierten CoMFA Methodik die aus letzterer entwickelte CoMSIA Methodik eingesetzt. Es konnten valide und statistisch signifikante CoMFA Modelle für den SERT (q2 = 0,538) und den NET (q2 = 0,445) erstellt werden. Das SERT Modell konnte mittels Region Focusing weiter verbessert werden (q2 = 0,674). Die erarbeiteten CoMSIA Modelle zeigen vergleichbare kreuzvalidierte Korrelationskoeffizienten mit q2 = 0,531 für den SERT und q2 = 0,502 für den NET. Die 3D QSAR Modelle beschreiben die molekularen Voraussetzungen für eine selektive Bindung an den SERT. Als Ausgangspunkt für Modifikationen wurde das Grundgerüst der N,N-Dimethyl-2-phenylsulfanyl-benzylamine gewählt. Zu ihnen gehört beispielsweise [11C]DASB, das sich kürzlich als vielversprechender PET-Tracer für den SERT erwiesen hat. 100 neue Strukturen wurden als selektive SERT-Liganden vorgeschlagen.Imaging the serotonin transporter (SERT) with Positron Emission Tomography (PET) provides a useful tool for understanding alterations of the serotonergic system. However, no optimal PET radiotracer for the SERT yet exists. The purpose of this work was the investigation of quantitative structure-activity relationships (QSAR) of SERT ligands. Distinctive features for high binding affinity at the SERT and at the structurally similar norepinephrine transporter (NET) were to be elucidated. The work was concluded with the design of potential new PET radiotracers for the SERT. A heterogeneous data set of 19 selective and non-selective SERT ligands was used. Affinity data for both the SERT and the NET was available. As a necessary prerequisite for 3D QSAR studies a reasonable alignment of the compounds was developed using GASP. It was based on an existing pharmacophore model. In addition to the widely used CoMFA method, the CoMSIA method, considered to be an extension of the former, was applied. Statistically reliable CoMFA models for both the SERT (q2 = 0.538) and the NET (q2 = 0.445) were developed, further improving the internal predictability by applying region focusing for the SERT (q2 = 0.674). The CoMSIA models yielded comparable cross-validated correlation coefficients of q2 = 0.531 for the SERT, and q2 = 0.502 for the NET. The resulting 3D QSAR models provide important information for lead optimisation with respect to selectivity enhancement and offer the opportunity to predict the binding affinity of new substances at both the SERT and the NET. Based on the fact that diphenyl sulphide derivatives such as [11C]DASB have recently proven to be promising PET ligands a rational modification of their N,N-dimethyl-2-phenylsulfanyl-benzylamine scaffold has been performed with regard to a possible F18 labelling. A series of 100 compounds were suggested. The novel compounds were predicted to be selective high affinity SERT ligands

Combined Structure-Based Pharmacophore and 3D-QSAR Studies on Phenylalanine Series Compounds as TPH1 Inhibitors

Tryptophan hydroxylase-1 (TPH1) is a key enzyme in the synthesis of serotonin. As a neurotransmitter, serotonin plays important physiological roles both peripherally and centrally. In this study, a combination of ligand-based and structure-based methods is used to clarify the essential quantitative structure-activity relationship (QSAR) of known TPH1 inhibitors. A multicomplex-based pharmacophore (MCBP) guided method has been suggested to generate a comprehensive pharmacophore of TPH1 kinase based on three crystal structures of TPH1-inhibitor complex. This model has been successfully used to identify the bioactive conformation and align 32 structurally diverse substituted phenylalanine derivatives. The QSAR analyses have been performed on these TPH1 inhibitors based on the MCBP guided alignment. These results may provide important information for further design and virtual screening of novel TPH1 inhibitors

A taxonomic revision of the African genus Desplatsia Bocq. (Malvaceae – Grewioideae)

A taxonomic revision of Desplatsia Bocq. (Malvaceae s. lat. Juss., subfamily Grewioideae Hochr., tribe Grewieae Endl.) based on about 800 herbarium specimens is presented. Desplatsia is a genus of trees and shrubs found in tropical West and Central Africa and is characterized by subulately divided stipules, the absence of an androgynophore, stamens that are fused to a tube at the base, and large and distinctive fruits that are dispersed by elephants. Four species are recognized (D. subericarpa Bocq., D. chrysochlamys (Mildbr. & Burret) Mildbr. & Burret, D. dewevrei (De Wild. & T.Durand) Burret and D. mildbraedii Burret) and 12 species names are placed into synonymy, two of which have been put into synonymy for the first time: D. floribunda Burret syn. nov. and D. trillesiana (Pierre ex De Wild.) Pierre ex A.Chev. syn. nov. All four species are widely distributed and their conservation status is assessed as Least Concern (LC). A key to the species, full species descriptions, illustrations, a specimen citation list and distribution maps are provided