Prototypes, molecular modification

The prototype for a new dmg is called a lead compound. Changing the stmcture of a lead compound is called molecular modification. A random screen (or blind screen) is a search for a pharmacologically active lead compound without having any information about what stmctures might show activity. The technique of relating a property of a series of compounds to biological activity is known as a quantitative structure-activity relationship (QSAR). 

The three prototype mixed p agonist/S antagonists described in this chapter have excellent potential as analgesics with low propensity to produce tolerance and dependence. The pseudotetrapeptide DIPP-NH2[ ] has already been shown to produce a potent analgesic effect, less tolerance than morphine, and no physical dependence upon chronic administration. In preliminary experiments, the tetrapeptides DIPP-NH2 and DIPP-NH2[T] were shown to cross the BBB to some extent, but further structural modifications need to be performed in order to improve the BBB penetration of these compounds. The Tyr-Tic dipeptide derivatives can also be expected to penetrate into the central nervous system because they are relatively small, lipophilic molecules. In this context, it is of interest to point out that the structurally related dipeptide H-Dmt-D-Ala-NH-(CH2)3-Ph (SC-39566), a plain p-opioid agonist, produced antinociception in the rat by subcutaneous and oral administration [72], As indicated by the results of the NMR and molecular mechanics studies, the conformation of the cyclic p-casomorphin analogue H-Tyr-c[-D-Orn-2-Nal-D-Pro-Gly-] is stabilized by intramolecular hydrogen bonds. There-... 

The CSC precursor build-up has been studied after modification of the silica gel surface from the gas phase. This gas phase modification involves the deposition of one molecular layer at the time. For thicker coatings, a cyclic procedure is needed. Liquid phase modification of the silica surface may also yield valuable ceramic precursors. The precursor molecular structure and layer thickness is controlled by other parameters compared to gas phase procedures. Parameters such as reaction solvent, silane concentrations and presence of water are of primal importance. Those have been discussed in detail in chapter 9. In this chapter, the application of silica modified with aminosilanes, will be discussed. The aminopropylsilica is used as a prototype compound for the production of ceramics by liquid phase chemical surface coating. 

Fortunately, TTF-TCNQ is a particularly suitable prototype, because of the amenability of the TTF donor molecule to chemical modification. Some of the possibilities are illustrated in Figure 1. Any or all of the sulfur heteroatoms can be replaced with selenium, and the terminal protons can be replaced with any of a wide variety of substituent groups. To study the role of interchain coupling, we seek to hold the molecular electronic structure and intrachain stacking patterns as nearly constant as possible, while introducing steric factors chosen so as to force changes in the crystal structure. 

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