Potencies

FIGURE 1-3 Relative potency and maximal efficacy of two drugs. Drug A is more potent, and drug B has a greater maximal efficacy. 

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The second application of the CFTI protocol is the evaluation of the free energy differences between four states of the linear form of the opioid peptide DPDPE in solution. Our primary result is the determination of the free energy differences between the representative stable structures j3c and Pe and the cyclic-like conformer Cyc of linear DPDPE in aqueous solution. These free energy differences, 4.0 kcal/mol between pc and Cyc, and 6.3 kcal/mol between pE and Cyc, reflect the cost of pre-organizing the linear peptide into a conformation conducive for disulfide bond formation. Such a conformational change is a pre-requisite for the chemical reaction of S-S bond formation to proceed. The predicted low population of the cyclic-like structure, which is presumably the biologically active conformer, agrees qualitatively with observed lower potency and different receptor specificity of the linear form relative to the cyclic peptide. 

Lead structure According to Valler and Green s definition a lead structure is a representative of a compound series with sufficient potential (as measured by potency, selectivity, pharmacokinetics, physicochemical properties, absence of toxicity and novelty) to progress to a full drug development program [12]. 

The term virtual screening or in silica screening is defined as the selection of compounds by evaluating their desirability in a computational model [17]. The desirability comprises high potency, selectivity, appropriate pharmacokinetic properties, and favorable toxicology. 

The purpose of this eornpuLer project is Lo examine several polynuclear aromatic hydrocarbons and to relate their electron density patterns to their carcinogenic activity. If nucleophilic binding to DN.A is a significant step in blocking the normal transcription process of DN.A, electron density in the hydrocarbon should be positively correlated to its carcinogenic potency. To begin with, we shall rely on clinical evidence that benzene, naphthalene, and phenanthrene... 

Enediynes hold substantial promise as anti cancer drugs because of their potency and selectivity Not only do they inhibit cell growth they have a greater tendency to kill cancer cells than they do normal cells The mechanism by which enediynes act involves novel chemistry unique to the C C—C=C—C C unit which leads to a species that cleaves DNA and halts tumor growth... 

Sweetness evaluation Sweetness potency Sweet n Low Sweet potato Sweet potatoes Sweetzyme Swelling Swimmingpool Swimming p o ols... 

This reversed-phase chromatography method was successfully used in a production-scale system to purify recombinant insulin. The insulin purified by reversed-phase chromatography has a biological potency equal to that obtained from a conventional system employing ion-exchange and size-exclusion chromatographies (14). The reversed-phase separation was, however, followed by a size-exclusion step to remove the acetonitrile eluent from the final product (12,14). 

Methylated Glucocorticoids. The preparation of 2a-methyl-9a- uorocortisol has been reported (76). This compound shows enhanced glucocorticoid activity and greatiy enhanced mineralocorticoid activity, so much that it surpasses aldosterone (19) ia sodium-retaining and potassium-excreting potency. Attention was then turned to the preparation of 6-methylated corticoids... 

Another series of antiinflammatory carboxyhc acids that ate derived from cortienic acid (107), a minor adrenal metabohte, has been described (104,105). Esterification of both the 17a-hydroxyl group and the carboxyhc acid of (107) were requited to develop a compound of high topical potency with low systemic activity. Peak activity was generally associated with a 17a-propionoxy group and a 17P- uoromethoxy carbonyl (eg, (108)), or 17P-methoxycarbonyl residue. 

As a class of compounds, the two main toxicity concerns for nitriles are acute lethality and osteolathyrsm. A comprehensive review of the toxicity of nitriles, including detailed discussion of biochemical mechanisms of toxicity and stmcture-activity relationships, is available (12). Nitriles vary broadly in their abiUty to cause acute lethaUty and subde differences in stmcture can greatly affect toxic potency. The biochemical basis of their acute toxicity is related to their metaboHsm in the body. Following exposure and absorption, nitriles are metabolized by cytochrome p450 enzymes in the Hver. The metaboHsm involves initial hydrogen abstraction resulting in the formation of a carbon radical, followed by hydroxylation of the carbon radical. MetaboHsm at the carbon atom adjacent (alpha) to the cyano group would yield a cyanohydrin metaboHte, which decomposes readily in the body to produce cyanide. Hydroxylation at other carbon positions in the nitrile does not result in cyanide release. 

Determination of the potency of Factor VIII is also difficult. This is normally measured by the abiUty of the sample to correct the clotting time of plasma deficient in Factor VIII. A number of methods and practices have evolved for this purpose (231), but these give very different results, particularly when activation of products may also occur (232). International standards have been used, but further standardization of the analytical method and harmonization of working standards is underway (233,234) under the auspices of the ISTH and the EC. 

Cascara sagrada is used as a cathartic. It is most useful when prepared as a fluid extract, and tends to be a mild laxative causing Htfle discomfort. However, on prolonged use it may result in characteristic melanotic pigmentation of the rectal mucosa. The bitter taste can be lessened, owing to neutralization of the acid constituents, if the ground substance is moistened and mixed with magnesium or calcium hydroxide. This treatment may lessen the potency of the preparation. 

This correlates narcotic potency, a gas s solubiUty in nerve tissue Hpids which can be approximated by its solubiUty in light oils such as oHve oil. 

The narcotic potency and solubiUty in oHve oil of several metabohcaHy inert gases are Hsted in Table 10. The narcotic potency, ED q, is expressed as the partial pressure of the gas in breathing mixtures requited to produce a certain degree of anesthesia in 50% of the test animals. The solubiUties are expressed as Bunsen coefficients, the volume of atmospheric pressure gas dissolved by an equal volume of Hquid. The Hpid solubiHty of xenon is about the same as that of nitrous oxide, a commonly used light anesthetic, and its narcotic potency is also about the same. As an anesthetic, xenon has the virtues of reasonable potency, nonflammability, chemical inertness, and easy elimination by the body, but its scarcity and great cost preclude its wide use for this purpose (see Anesthetics). 

Table 10. Narcotic Potency and Solubility in Olive Oil of Some Metabolically Inert Gases ...

ED q, narcotic potency, is expressed as the partial pressure of a gas in breathing mixtures requited to produce a certain degree of anesthesia in 50% of the test animals. 

Astemi2ole (10) has further been modified into a series of 4-phenylcyclohexylamine compounds, resulting in the synthesis of cabastine, for example. Cabastine is a highly active compound and its geometric isomers are also active, demonstrating the stereoselectivity of histamine receptors toward chiral ligands. The > S, 4 R-levo antipode of cabastine was the most active, and therefore this isomer, levocabastine (13), has been chosen for further development. Because of high potency, levocabastine has been developed for topical appHcation such as eye drops and nasal spray. 

P-Endorphin. A peptide corresponding to the 31 C-terminal amino acids of P-LPH was first discovered in camel pituitary tissue (10). This substance is P-endorphin, which exerts a potent analgesic effect by binding to cell surface receptors in the central nervous system. The sequence of P-endorphin is well conserved across species for the first 25 N-terminal amino acids. Opiates derived from plant sources, eg, heroin, morphine, opium, etc, exert their actions by interacting with the P-endorphin receptor. On a molar basis, this peptide has approximately five times the potency of morphine. Both P-endorphin and ACTH ate cosecreted from the pituitary gland. Whereas the physiologic importance of P-endorphin release into the systemic circulation is not certain, this molecule clearly has been shown to be an important neurotransmitter within the central nervous system. Endorphin has been invaluable as a research tool, but has not been clinically useful due to the avadabihty of plant-derived opiates. 

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