Structural dissimilarity

Lack of perfect specificity in carrier-solute recognition provides for the possibility that structurally similar solutes may compete for carrier availability. Analysis of competitive [Eq. (18)] and noncompetitive [Eq. (19)] inhibition as well as cooperativity effects (allosteric modulation by structurally dissimilar solutes) on carrier-mediated solute flux is equivalent to assessment of the velocity of enzyme reactions. 

Structurally dissimilar, active molecules provide more information about the site than a series of active close structural homologs. 

Although these effects of lithium on PKC isozymes and MARCKS are striking, a major problem inherent in neu-ropharmacologic research is the difficulty in attributing therapeutic relevance to any observed biochemical finding. It is thus noteworthy that the structurally dissimilar... 

The experimentally observed substituent effect on the triplet and singlet quantum yields in the complete series of methyl-substituted dioxetanes, as well as the predicted C—C and 0—0 bond strength for the four-membered peroxidic rings , have led to the hypothesis that a more concerted, almost synchronized, decomposition mechanism should lead to high excitation quantum yields (as in the case of tetramethyl-l,2-dioxetane), whereas the biradical pathway presumably leads to low quantum yields (as in the case of the unsubstituted 1,2-dioxetane)" . However, it appears that this criterion of concertedness is difficult to apply generally to structurally dissimilar dioxetane derivatives. 

Kay P., P.A. Blackwell, and A.B.A. Boxall (2004). Pate of veterinary antibiotics in a macro-porous tile drained clay soil. Environmental Toxicology and Chemistry 23 1136-1144. Keller B.J., H. Yamanaka, and R.G. Thurman (1992). Inhibition of mitochondrial respiration and oxygen-dependent hepatoxicity by six structurally dissimilar peroxisomal proliferating agents. Toxicology 71 49-61. 

Metabolic activators and inhibitors are structurally dissimilar to substrates. These effectors exert regulatory control over catalysis by binding at an allosteric site quite distinct from the catalytic site. Such heterotropic interactions are mediated through conformational changes, often involving subunit interactions. Allosteric effectors can alter the catalytic rate by changing the apparent substrate affinity (K system) or by altering the... 

The presence of two structurally dissimilar groups within a single molecule is the most fundamental characteristic of surfactants. The surface behavior (surface activity) of the surfactant molecule is determined by the makeup of the individual groups, solubility properties, relative size, and location within the surfactant molecule. 

Based on data cited previously it appears that TPA s primary effect is at the cell surface (55, 56). This does not exclude the possibility that TPA is transported and metabolized to an "active" intermediate, which then affects glycosyltransferase activity. However, it is possible (particularly in light of the structural dissimilarity between TPA and RA) that these compounds affect glycoconjugate metabolism in different ways. 

Fig. 11.18. Four metabotropic glutamate receptor ligands (A-D) and their structural dissimilar parts (a-d) [149]. For the latter, the COSMO (T-surfaces are shown for comparison.

A frequently cited example of an important natural-product-derived drag is the neuromuscular blocker d-tubocurarine, derived from the South American plant curare, which was used by South American Indians as an arrow poison (see Chapter 26). Tubocurarine led to the development of decamethonium, which, although structurally dissimilar to tubocurarine, was nevertheless synthesized based on the then prevalent presumption that tubocurarine contained two quaternary nitrogens. Similarly, synthetic local anesthetics, such as lidocaine, benzocaine, and dibucaine, were synthesized to mimic the nerve-blocking effect of cocaine, a natural alkaloid obtained from the leaves of Coca eroxylum, but without the adverse side effects that have led to its abuse. 

The NMR spectra of the major groups of indole alkaloids are discussed below. Section J describes the NMR spectral characteristics of a variety of indole alkaloids which, although biogenetically related to alkaloids in Sections A-I, are discussed separately because of formal structural dissimilarities. 

Formazan dyes bear a formal resemblance to azo dyes, since they contain an azo group, but have sufficient structural dissimilarities to be considered as a separate class. The most important formazan dyes are the metal complexes, particularly copper complexes, of tetradentate formazans (see Section 2.10.3). They are used as reactive dyes for cotton (12) is a representative example. 

Fig. 13.3. This figure provides another example of the incongruity of fossil records and molecular genealogy. Using humans as a standard, all mammals that purportedly are closely related have relaxins that are not more closely related to human relaxin than to that of skates and sharks. Since skates and sharks have been around in the Devonian period 380,000,000 years ago, the structural dissimilarity of the various relaxin molecules would suggest that the branching point between humans, horses, rats, etc., as well as sharks would have occurred 380,000,000 years ago. Conversely, the mammalian explosion is placed at about 60,000,000 years, which would force all the molecular genealogy lines to converge at a point 60,000,000 years ago, giving us a 300,000,000 years uncertainty. This difference is not trivial, it represents 3/3 of the total time of macro-organismic development.

Until about 1980, it was widely accepted that the benzodiazepine structure was a prerequisite for the anxiolytic profile and for the recognition of and binding to the benzodiazepine receptor. More recently, however, a chemically unrelated drug, the cyclopyrrolone zopiclone, has been shown to be a useful sedative hypnotic with a benzodiazepine-like profile. Other chemical classes of drugs that are also structurally dissimilar to the benzodiazepines (e.g. triazolopyridazines) have also been developed and shown to have anxiolytic activity in man these non-benzodiazepines also act via the benzodiazepine receptor. Thus the term "benzodiazepine receptor ligand" has been introduced to describe all drugs, irrespective of their chemical structure, that act on benzodiazepine receptors and thereby modulate inhibitory transmission in the brain. 

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