Development from biochemically active molecules

Second generation COMT inhibitors were developed by three laboratories in the late 1980s. Apart from CGP 28014, nitrocatechol is the key structure of the majority of these molecules (Fig. 3). The current COMT inhibitors can be classified as follows (i) mainly peripherally acting nitrocatechol-type compounds (entacapone, nitecapone, BIA 3-202), (ii) broad-spectrum nitrocatechols having activity both in peripheral tissues and the brain (tolcapone, Ro 41-0960, dinitrocatechol, vinylphenylk-etone), and (iii) atypical compounds, pyridine derivatives (CGP 28014,3-hydroxy-4-pyridone and its derivatives), some of which are not COMT inhibitors in vitro but inhibit catechol O-methylation by some other mechanism. The common features of the most new compounds are excellent potency, low toxicity and activity through oral administration. Their biochemical properties have been fairly well characterized. Most of these compounds have an excellent selectivity in that they do not affect any other enzymes studied [2,3]. 

The development of HR-MAS probes has resulted in several technical developments extending beyond the analysis of SPS products. HR-MAS NMR has also been used for structure determination of very small samples containing submicrogram quantities of biological molecules 35 it has been used for the biochemical characterization of tissue samples in normal and disease states 36 and more recently it has been used in a screening role to identify substances with binding activity from a mixture of compounds,37 as described later in this review. 

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