FURTHER STRUCTURAL MODIFICATION

The results in table 2.6 show that the rates of reaction of compounds such as phenol and i-napthol are equal to the encounter rate. This observation is noteworthy because it shows that despite their potentially very high reactivity these compounds do not draw into reaction other electrophiles, and the nitronium ion remains solely effective. These particular instances illustrate an important general principle if by increasing the reactivity of the aromatic reactant in a substitution reaction, a plateau in rate constant for the reaction is achieved which can be identified as the rate constant for encounter of the reacting species, and if further structural modifications of the aromatic in the direction of further increasing its potential reactivity ultimately raise the rate constant above this plateau, then the incursion of a new electrophile must be admitted. 

The significance of establishing a limiting rate of reaction upon encounter for mechanistic studies has been pointed out ( 2.5). In studies of reactivity, as well as settii an absolute limit to the significance of reactivity in particular circumstances, the experimental observation of the limit has another dependent importance if further structural modification of the aromatic compound leads ultimately to the onset of reaction at a rate exceeding the observed encounter rate then a new electrophile must have become operative, and reactivities established above the encounter rate cannot properly be compared with those measured below it. 

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-... 

Further Structural Modifications P450 Hydroxylase Enzymes... 

Further structural modifications were made on the a-bromoacylamide structure (18). For 14 derivatives where R is varied from simple alkyl to such highly branched... 

In other approaches, close to 30 QDO derivatives were carefully selected from Monge s more than 200-quinoxaline library in order to evaluate its anti-T. cruzi activity. The study, performed in two different T. cruzi strains, showed that compounds 32-35 (Fig. 12) are an excellent starting point for further structural modifications [132,133]. Some reduced derivatives, Qx, displayed relevant activities but these compounds could be also toxic in mammal... 

Selection of the azidomethyl glycol (243) for development as a possible clinical candidate for oral administration necessitated further structural modification of the A -terminus due to the acid lability of the BOC group, and the susceptibility of the Phe-His bond towards cleavage by chymotryp-... 

Recently, a new type of nonpeptidic 8 agonist (182), which lacks a basic nitrogen, was identified by high throughput screening (592). Further structural modification of this lead compound to improve its water solubility led to a series of amide derivatives (e.g., 183) with modest 8-receptor affinity (IC50 = 37-256 nAf) and in vivo potency comparable to TAN 67 (593). 

Mu-Receptor Antagonists Derived from Somatostatin. Potent p-opioid antagonists have been identified that are derivatives of somatostatin rather than of an opioid peptide (see Ref 656 for a review). Somatostatin exhibits low affinity for opioid receptors, and the potent somatostatin analog SMS-201,995 (D-Phe-cycZo[CyS Phe-D-Trp-Lys-Thr-Cys]-Thr-ol) was found to be an antagonist at p, opioid receptors (940). Further structural modification yielded a series of peptides with the general structure D-Phe-cycZo[Cys-Tyr-D-Trp-X-Thr-Pen]-ThrNH, where X = Lys, Om, or Arg in CTP, CTOP (19, Fig. 7.4), and... 

Further structural modifications of chlorbetamide and chlorphenoxamide molecules resulted in a series of mono- and disubstituted dichloroacetamides [20-27],... 

In many fields of drug development, nature has supplied the first effective agents and the first clues for further structural modification by syntheses. This has been true also in the diuretic field but to a much less extent than in many other areas of medicinal chemistry. 

As to the second question—i.e., the necessity for eliciting an initial psychotomimetic response prior to the alleviation of the mental depression—we feel that this is not an essential prerequisite and that further structural modification might produce an effective antidepressant agent in this series which is devoid of potent psychotogenic properties. Some recent work by Hidalgo et al. (49, 50) indicates that certain related piperidyl dioxolanes ... 

Suggest further structural modifications to address any molecular regions that you deem to be potentially problematic for a completely optimized profile (assuming for the moment that a once-a-day orally bioavaUable product is a crucial part of the desired indication). 

FURTHER STRUCTURAL MODIFICATION Pressure, temperature and chemical influence... 

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