3 The structural model allowed investigation of the molecular basis of receptor functions, such as ligand binding, signal transduction via G protein-coupling, and regulation (for example, of desensitization).5 First, analyses of sequcnce-structure-function relationships were performed. In order to correlate

specific components of receptor function with specific amino acids, the effects of mutations introduced into the “wild type” sequence by in vitro site-directed mutagenesis were examined. It was demonstrated that DNA sequence differences Inhibitors,research,lifescience,medical caused differences in receptor function. Mutations were shown (i) to significantly affect, the ability of the receptor to bind ligands with a characteristic specificity and affinity; (ii) to activate characteristic and specific Inhibitors,research,lifescience,medical effectors; and (iii) to undergo functional regulation.6 At this stage, mutations were conceived primarily as the result, of experimental intervention

and as an important tool for analyzing the functional content of DNA sequence information. The possibility that mutations might, occur as natural phenomena that confer a spectrum of natural functional variations was simply not part, of the picture or Inhibitors,research,lifescience,medical even an acknowledged hypothesis. For as long as one could think of, pharmacological effects were conceived as specific, uniform values, which were defined by a mean value (the average of all individual values) and a standard error (an indication of the extent of deviation of the individual Inhibitors,research,lifescience,medical values from the mean, ie, the usual scattering of these values). Such variability was supposed to reflect, deviation from the true value as a result of confounding parameters, which introduced the errors in the Inhibitors,research,lifescience,medical process of measurement. At its extreme, the mean value described an effect, that did not, apply to any of the individuals who participated in the experiment. A gradual change in concept, to the conscious notion of individual variability at the pharmacological,

clinical, and molecular level, and the acceptance of variation as the frame of reference and object of research did not Etomidate emerge until the very early days of the Human Genome Project. On the basis of vision more than fact, it was AZD0530 hypothesized that differences in UNA sequence – the most basic level of molecular information – were related to individual genetic differences in drug response.6,7 The hypothesis of a biochemical individuality of man and its relationship to pharmacogenetic phenomena had already been raised in the early 1900s8 and first observations of individual differences in the response to the same drug had been made by Pythagoras as early as the fifth century BC.9 However, these observations were generally considered exceptions from the rule.