The first structure-activity relationships

Interestingly, highly stereospecific interaction of BIBP 3226 with the human Y1 receptor expressed in SK-N-MC cells could be shown by the drastically reduced receptor binding affinity (h Y1, IC5o 10 000 nM) of the corresponding (S)-enantiomer of BIBP 3226. 

The affinity of BIBP 3226 for NPY receptor types has been investigated in a variety of tissues and cell lines. BIBP 3226 displayed K, values of 5.1 and 6.8 nM for the human and rat Y1 receptors (Wieland et al., 1995) and virtually no affinity (A) 10 000 nM) for Y2, Y3 and Y4 receptors (see Table 1 Wieland et al., 1995 Doods et al., 1996). In addition, no measurable affinity could be detected for a wide variety of other receptors or enzyme systems (see Table 2). 

As listed in Table 1, the pA), values of BIBP 3226 for Y1 receptors ranged from 7.0 to 8.5. Concentration up to 10 pM had no effect on Y2, Y3 and Y4 receptors. Summarizing the receptor data, it can be concluded that BIBP 3226 is a highly selective Y1 antagonist. 

With respect to CNS effects of BIBP 3226, only limited data are available. Since BIBP 3226 does not penetrate the blood-brain barrier, it has been injected directly into the hypothalamus in order to observe the effect of this compound on NPY-induced feeding. However, we and others were not able to demonstrate unambiguously an effect of BIBP 3226 on feeding since after intracerebroventricular or paraventricular nucleus application, unwanted side effects, e.g. barrel rolling, occur. 

Type Tissue/cell line Radioligand P K Reference Tissue Agonist P Kb Reference 

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The Schreiber synthesis is particularly noteworthy in that the absolute configuration of discodermolide was assigned unambiguously, and through the preparation of numerous analogues the first structure-activity relationship study was possible [35,44], Their synthesis of the unnatural antipode (ent-1) also led to the unexpected discovery that it causes cell cycle arrest in the S-phase [107],... 

In order to establish the first structure-activity relationships around our lead compound BIBP 3226, four arbitrarily selected structural elements (N-terminus, amino acid, C-terminus, backbone) were defined (Figure 3) and modified individually while keeping the rest of the molecule constant. First results of these structural variations are summarized below ... 

The earliest structure-activity relationships indicated that the transplatinum geometry is inactive— significantly higher doses must be given before any therapeutic effect is seen. In 1991, it was reported that alteration of amine structure and the introduction of sterically hindered amines produced cytotoxicity similar to that of cisplatin.162 The first examples used planar amines and a variety of tra s-[PtCl2(L)(L )] compounds have been synthesized and evaluated ((21)-(26), Figure 12).163... 

Immediately after the first few carcinogenic hydrocarbons were identified, scientists puzzled over the developing structure-activity relationships and tried to identify the structural features of the hydrocarbons which are associated with their carcinogenic activity. 

Another extension is the descriptor selection procedure designed to enhance the stability and predict vity of the PLSR models. Its aim is to minimize the info-noise that can dilute and distort the true structure-activity relationship. The procedure involves two phases. The first phase consists of the elimination of the low-variable descriptors that have the same value for all but a few (2-3) compounds in the training set. Such descriptors cannot provide useful statistical information and instead simply help to fit these particular compounds into a model, thus decreasing its predictivity. This filtering is performed entirely in the X-space, without regard for the aetivity values. In the optional second phase, the descriptor... 

It has been nearly 40 years since the quantitative structure-activity relationship (QSAR) paradigm first found its way into the practice of agrochemistry, pharmaceutical chemistry, toxicology, and eventually most facets of chemistry (1 )Its stayingpower may be attributed to the strength of its initial postulate that activity was a function of structure as de-... 

Other pharmacological activities have also been correlated with quantum-chemically derived descriptors. For instance, the quantitative structure-activity relationship developed for the antibacterial activity of a series of monocyclic (i-lactam antibiotics included the atomic charges, the bond orders, the dipole moment, and the first excitation energy of the compound [103]. The fungicidal activity of A3-l,2,4-thiadiazolines has been correlated with an index of frontier orbital electron density derived from semi-empirical PM3 molecular orbital calculations [104],... 

The irreversible HDAC inhibitor TPX was first isolated as a fungal metabolite that induced morphological reversion of v-sis-transformed NIH 3T3 cells [10]. Using the known structure-activity relationship between other HDAC inhibitors as a guide, a TPX affinity reagent was synthesized and used to identify its target protein as a HDAC [11]. 

Electrophilic aromatic substitution is a situation in which it is useful to discuss TS structure in terms of a reaction intermediate. The ortho, para, and meta directing effects of aromatic substituents were among the first structure-reactivity relationships to be developed in organic chemistry. Certain functional groups activate aromatic rings toward substitution and direct the entering electrophile to the ortho and para positions, whereas others are deactivating and lead to substitution in the meta position. The bromination of methoxybenzene (anisole), benzene, and nitrobenzene can serve as examples for discussion. 

First structure-activity relationships relating to crop protection targets were reported by Fisher in 1984 [47]. This study showed that avermectin Bia was somewhat more active then mUbemydn D against Tetranychus urticae, Hdiothis virescens, and Mdoidogyne incognita. As milbemycin D can be viewed as the 22,23-dihydro-13-desoxy derivative of avermectin Bib, this comparison reflects the influence of the disaccharide portion of avermectins on their activity as pesticides. 

This makes it clear that - independent of the strategy - screening hits rarely fulfill all necessary criteria for a new lead structure. Medicinal chemists have to analyze the screening results (usually structural formulas with corresponding biological or biochemical data) to derive a first structure-activity relationship (SAR) hypothesis. 

In the examination of the toxic tall larkspurs, several adjustments of the research approach were necessary to develop an efficient research plan. First, the etiology of tall larkspur poisoning is well established and several species of tall larkspur are clearly recognized as threats to livestock. Furthermore, research information exists on the isolation of toxic components from both Aconitum and Delphinium species and on the toxicity, structure/activity relationships and mode of action of the alkaloids obtained from toxic larkspurs (see previous discussion). Less information is available about toxins present in the... 

A challenging task in material science as well as in pharmaceutical research is to custom tailor a compound s properties. George S. Hammond stated that the most fundamental and lasting objective of synthesis is not production of new compounds, but production of properties (Norris Award Lecture, 1968). The molecular structure of an organic or inorganic compound determines its properties. Nevertheless, methods for the direct prediction of a compound s properties based on its molecular structure are usually not available (Figure 8-1). Therefore, the establishment of Quantitative Structure-Property Relationships (QSPRs) and Quantitative Structure-Activity Relationships (QSARs) uses an indirect approach in order to tackle this problem. In the first step, numerical descriptors encoding information about the molecular structure are calculated for a set of compounds. Secondly, statistical and artificial neural network models are used to predict the property or activity of interest based on these descriptors or a suitable subset. 

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