Activity of drugs

The work by Hammett and Taft in the 1950s had been dedicated to the separation and quantification of steric and electronic influences on chemical reactivity. Building on this, from 1964 onwards Hansch started to quantify the steric, electrostatic, and hydrophobic effects and their influences on a variety of properties, not least on the biological activity of drugs. In 1964, the Free-Wilson analysis was introduced to relate biological activity to the presence or absence of certain substructures in a molecule. 

The modification and enhancement of biological activity of drugs and hormones by fluorination represent one of the most fruitful recent developments in medicinal chemistry. Its first successes and most interesting subsequent developments were in the steroid field. Almost every new technique of introducing fluorine into organic compounds has been applied in this area and, as a result of both the gross and subtle chemical differences which steroids display at different locations of the nucleus, has produced a wealth of new chemistry. 

The strange amino-acid (4) is a fat version of phenylalanine (5) having a side chain which is rigid and inert, but which is also space filling rather than flat. Optically active (4) was needed to study peptide conformation and the biological activity of drugs. 

Hansch C, Clayton JM. Lipophilic character and biological activity of drugs. II. The parabolic case. J Pharm Soc 1973 62 1-21. 

Again, this can affect the doses of certain dmgs that are administered to patients. Various diseases (eg, cirrhosis of the liver) can affect the activities of drug-metabohz-ing enzymes, sometimes necessitating adjustment of dosages of various drugs for patients with these disorders. 

C. Hansch and W.J. Dunn III, Linear relationships between lipophilic character and biological activity of drugs. J. Pharmaceut. Sci., 61 (1972) 1-19. 

Krsiak, M. Timid singly-housed mice Their value in prediction of psychotropic activity of drugs. Brit J Pharmacol 55 141-150, 1975. 

Nevertheless, numerous QSARs involve other lipophilicity dependencies to model biological activity of drugs, among which Kubinyi s bilinear relationship must be quoted [338] (see Ref 109 for a review). However, the database collected by Hansch s group showed in 1993 [339] that only 15% of the biological QSARs do not imply any lipophilicity term. Hence, lipophilicity is clearly a major determinant of biological activity [340]. 

Snyder, S. H., and Merril, C. T. (1965) A relationship between the hallucinogenic activity of drugs and their electronic configuration. Proc. Natl. Acad. Sci. USA, 54 258-266. 

These refinements in our knowledge of brain penetration and CNS activity of drugs feature prominently in a major medicinal review of the blood-brain barrier [14]. In vivo perfusion studies on the rate of brain uptake of several non-steroidal anti-inflammatory drugs in rats with increasing concentration of albumin in the perfusate clearly demonstrate the effect of plasma protein binding on the rate (in addition to the extent at steady-state) of brain uptake [15]. 

Objectives Optimize biological activity of drugs Find new active lead compounds Characteristics Response in isolated systems Effects are specific and well defined Specific mechanism of action Receptor is known in most cases Techniques Hansch Approach Multivariate Analysis Computerized molecular modeling Estimate rates of fate processes Analyze Processes Whole organism response Net effects (mortality growth, etc.) Specific nonspecific mechanisms Receptor unknown in most cases Hansch Approach Multivariate Analysis Molecular modeling not applied... 

Hansch C and Dunn WJ (1972) Linear Relationships Between Lipophilic Character and Biological-Activity of Drugs. J Pharm Sci 61 pp 1-19. 

Hao M, Zhao Y, Chen P et al (2008) Structure-activity relationship and substrate-dependent phenomena in effects of ginsenosides on activities of drug-metabolizing P450 enzymes. PloS... 

Ariyoshi T, Ideguchi K, Iwasaki K, et al. 1975. Relationship between chemical structure and activity. II. Influences of isomers of dichlorobenzene, trichlorobenzene and tetrachlorobenzene on the activities of drug-metabolizing enzymes. Chem Pharm Bull 23 82... 

Whilst giving some ideas of the penetration into the brain, such data are limited in understanding the CNS activity of drugs. Whole brain partitioning actually repre-... 

Drugs are considered to act additively when the activity of drugs in combination are equal to the sum of their independent activity. The overall effect of two antimicrobial drugs can be less (antagonism) or more (synergism) than the sum effect. 

E. J. Ariens, W. Sondijn, P. Timmermans (Eds.) (1983). Stereochemistry and Biological Activity of Drugs. Oxford Blackwell. 

A considerable number of enzymes occupy a central and crucial role in the activity of drugs. Dihydrofolate reductase, an enzyme involved in purine and amino acid biosynthesis, is the target of antibacterial sulfanilamides, which act both as bacteriostatics and antimalarials. These drugs act on the enzyme in different ways, some being so-called antimetabolites (i.e., reversible enzyme inhibitors). Some diuretics act on carbonic... 

Pauli KD, Shoemaker RH, Hodes L et al. Display and analysis of patterns of differential activity of drugs against human tumor cell lines development of mean graph and COMPARE algorithm. J Aar/ Cancer Inst 1989 81 1088-1092. 

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