Studies on the Structure-Activity Relationship

Cerletti, A., Taeschler, M., and Weidmann, H. (1968) Pharmacologic studies on the structure-activity relationship of hydroxyindole alkylamines. Adv. Pharmacol., 6B.233-246. 

Mills RA, Minis CD, Dannan GA, et al. 1985. Studies on the structure-activity relationships for the metabolism of polybrominated biphenyls by rat liver microsomes. Toxicol Appl Pharmacol 78 96-104. 

These controversial findings inspired numerous subsequent studies on the structure-activity relationship of catalytically active compounds. Very detailed mechanistic studies on the catecholase activity of a series of structurally related dicopper(II) complexes have also been published by Casella and co-workers [37-40], who have grouped together different mechanisms earlier proposed for the catecholase activity of dicopper(II) complexes, as shown in Scheme 5.2. 

Yamamura, S., Oda, K., Mizoguchi, X, Saito, S., Iwasawa, Y., Kiyomoto, A. Study on the structure-activity relationships of adrenergic, beta-mimetic benzylamine derivatives. V. 9-aryl-l/7-2,3,7,8,9,10-hex-ahydro-benzo[d,e]quinoUnes. Chem. Pharm. Bull. 1979, 27, 858-869. 

In 1962, Hansch, Maloney and Fujita [Hansch, Maloney et al, 1962] published their study on the structure-activity relationships of plant growth regulators and their dependency on Hammett constants and hydrophobidty. Using the octanol/water system, a whole series of partition coefficients was measured and, thus, a new hydrophobic scale was introduced for describing the inclination of molecules to move through environments characterized by different degrees of hydrophilicity such as blood and cellular membranes. The delineation of Hansch models led to explosive development in QSAR analysis and related approaches [Hansch and Leo, 1995]. This approach known with the name of Hansch analysis became and it still is a basic tool for QSAR modeling. 

Studies on the structure-activity relationships revealed the functional groups at the position C-4, C-6 and C-13 of scopadulan skeleton to be playing important roles for exhibition of biological activities. 

Several studies on the structure-activity relationships (SAR) of cannabinoids have been recently published [34-37]. Three important features have been determined for classical and nonclassical cannabinoids a side-chain of three to seven carbon atoms in the 3-position of the phenol, a phenolic hydroxyl, and a suitable conformation or substituents in the C 9 position. However, not all these features are necessarily required to produce analgesic effects. 

From the perspective of structure-activity relationships, it is interesting that both motilin and motilides act as agonists for the motilin receptor, even though they have very different chemical structures (Fig. 17). Studies on the structure-activity relationship of motilin revealed that four hydrophobic residues, Phe 1, Val 2, He 4, and Tyr 7, of the motilin N-terminal region are most essential for its activity [38-41]. 

Extensive studies on the structure-activity relationships (SAR) in a series of compounds derived from squalestatins 1 (zaragozic acid A) (25) and 3 (27) have been performed, focusing on the role of the carboxylic acids at C-3, C-4 and C-5 positions of [15 -(la,3a,4p,5a,6a,7P)]-4,6,7-trihydroxy-2,8-dioxabicyclo-[3.2.1 ]-octane-3,4,5-tricarboxylic acid [58-61]. Consequently, the modification of the carboxylic acid at C-5 in squalestatin 1 analogues was not tolerated, but the carboxylic acids at C-3 and C-4 were not absolutely required for the retention of squalene synthase inhibitory activity [58J. 

N K Pardo A, Vivas S, Espana F and Fernandez-Alonso JI, Studies on the structure-activity relationship of tricyclic psychodrugs. III. Dissociation constants, Afinidad, 29, 640-642 (1972) Persson B-A, Extraction of amines as complexes with inorganic anions, Acta Pharm. Suecica, 5, 335-342 (1968). 

Studies on the structure-activity relationship of a chemical reaction often provide valuable information regarding its chemical mechanism. Quantitative structure-activity relationship... 

Kara, T.J. Further studies on the structure-activity relationships of amino acids in fish olfaction. Comp. Biochem. Physiol.. 1977, 56A, 559-565. 

Studies on the structure-activity relationship clearly demonstrate that the biological activity generally falls sharply with the introduction of any substituents in po-... 

One problem was that three different groups had to be connected regioselec-tively to the 1,2- and 3-positions of the benzene ring in the phthaloyl moiety. An iodine atom was introduced selectively into the 3-position of the phthaloyl moiety by a palladium-catalyzed reaction in the presence of a specific substituent in the 2-position. On the basis of the structure-activity relationship, the introduction of lipophilic alkyl substituents, including fluorine atoms, seemed to increase the activity though a practical method of introduction was not available. The overcoming of such difficulties led to dramatic advances in terms of a more detailed study on the structure-activity relationship as well as the establishment of a facile synthetic method that provided various new derivatives. 

Our studies on the structure-activity relationships for compounds related to 1 (See for example Figure 1) show that very small structural changes result in a loss of the activity. 

---