Despite its importance and all the considerable efforts made, the progress in drug discovery is limited. One main reason for this is the partly questionable data quality. Models relating biological activity and structures and in silico predictions rely on precisely and accurately measured binding data. However, these data vary so strongly, such that only variations by orders of magnitude are considered as unreliable. This can certainly be improved considering the high analytical performance in pharmaceutical quality control. Thus the principles, properties and performances of biochemical and cell-based assays are revisited and evaluated. In the part of biochemical assays immunoassays, fluorescence assays, surface plasmon resonance, isothermal calorimetry, nuclear magnetic resonance and affinity capillary electrophoresis are discussed in details, in addition radiation-based ligand binding assays, mass spectrometry, atomic force microscopy and microscale thermophoresis are briefly evaluated. In addition, general sources of error, such as solvent, dilution, sample pretreatment and the quality of reagents and reference materials are discussed. Biochemical assays can be optimized to provide good accuracy and precision (e.g. percental relative standard deviation <10 %). Cell-based assays are often considered superior related to the biological significance, however, typically they cannot still be considered as really quantitative, in particular when results are compared over longer periods of time or between laboratories. A very careful choice of assays is therefore recommended. Strategies to further optimize assays are outlined, considering the evaluation and the decrease of the relevant error sources. Analytical performance and data quality are still advancing and will further advance the progress in drug development.
The development of privileged molecular scaffolds efficiently mimicking reverse turn motifs and thus increasing both binding and selectivity and enabling the elucidation of the bioactive conformation of a natural peptide has attracted remarkable interest. The frequent occurrence of proline in various turn patterns initiated the design of proline-based reverse turn mimetics. As a structural hybridization of a highly potent type VI beta-turn inducer 1 with saturated spirocyclic lactams 3 efficiently mimicking type II beta turns, we developed a versatile synthetic route towards unsaturated spirocyclic lactams of type 2, when Seebach's self-reproduction of chirality methodology was combined with a peptide coupling reaction and Grubbs' ring-closing metathesis. By this means, a variety of model peptides with six- up to nine-membered lactam rings were accessible following a uniform pathway. Introduction of suitably protected templates into solid-phase peptide synthesis gave rise to unsaturated spirocyclic analogues of the naturally occurring neuropeptide neurotensin. Spectroscopic investigations as well as DFT calculations on a high level of theory revealed a remarkable dependence of the reverse-turn inducing potency on the ring size. While the secondary structure of the unsaturated spirocyclic epsilon-lactam 12 closely agrees with the reference gamma-lactam 3 a, the unsaturated delta-lactam 11 serves as an extraordinarily potent beta-turn inducer which is even superior to beta-lactams of type 3 b. The eight-membered unsaturated spirocyclic lactam 13 adopts a conformation almost ideally matching the prerequisites for a canonical type II beta turn with the highest stability of the whole series. In contrast, the nine-membered spirolactam 14 represents a scaffold with a high conformational flexibility.
Bereits kurze Zeit nach der wegweisenden Entdeckung der physiologischen Bedeutung von Dopamin durch Arvid Carlsson (Abb. 1, links) erkannte der Wiener Pharmakologe Oleh Hornykiewicz (Abb. 1, Mitte) dessen pathophysiologische Relevanz für Morbus Parkinson. Zusammen mit seinem Kollegen Herbert Ehringer konnte er in post-mortem-Gewebe von Parkinson-Patienten einen konsistenten Verlust von Dopamin im Nucleus caudatus und Putamen nachweisen [1]. Auf Basis dieser Erkenntnis testete Hornykiewicz in Ende der 1950er Jahre gelang es dem Göteborger Pharmakologen Arvid Carlsson im Tierexperiment zu zeigen, dass Dopamin als Neurotransmitter im Striatum eine zentrale Bedeutung für die Steuerung kontrollierter Bewegungen besitzt. Für diese und weitere grundlegende Erkenntnisse über die Rolle von Dopamin wurde er im Jahr 2000 mit dem Nobelpreis für Medizin ausgezeichnet. Kooperation mit dem Neurologen Walther Birkmayer zum ersten Mal die i.v.-Gabe von L-DOPA an Parkinson-Patienten und begründete mit dem großen Erfolg dieser Studie die therapeutische Substitution von Dopamin mit L-DOPA: "Der Effekt einer einmaligen intravenösen L-DOPA-Gabe beim Parkinson-Syndrom bestand, kurz gesagt, vor allem in einer gänzlichen Aufhebung bzw. wesentlichen Verringerung der Akinese. Patienten, die sich aus dem Liegen nicht aufsetzen, aus dem Sitzen nicht aufstehen, vom Stehen nicht zum Gehen starten konnten, brachten diese Leistungen nach L-DOPA-Gaben leicht zustande." [2] Der große Erfolg der L-DOPA-Therapie und die in der Monotherapie notwendigen hohen Dosen erzeugten Mitte der 1960er Jahre unerwarteter Weise einen beträchtlichen Bedarf an dieser damals in nur kleinen Mengen verfügbaren Aminosäure. Ausgehend von dem reichlich vorhandenen Vanillin konnte durch eine Erlenmeyer-Azlacton-Synthese zwar das racemische DL-DOPA effizient hergestellt werden, allerdings stellte die nachfolgende Enantiomerentrennung ein für die industrielle Produktion eher unerwünschtes Verfahren dar. Deshalb entwickelte die Arbeitsgruppe von William S. Knowles (Abb. 1, rechts) bei Monsanto über ei-
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