Quantitative structure-property relationship pharmacological activity

Work on the relationship between chemical structure and pharmacological activity of morphinans to 1966 has been reviewed by Hellerbach et al. s) and morphinans with antagonist properties were reviewed in 1973.(158) As is the case for 4,5-epoxymorphinans (Chapter 2) and benzomorphans (Chapter 4), molecular geometry is the major structure-biological activity influence, although the nature of the N-substituent imparts significant qualitative and quantitative variations in morphinan pharmacology. 

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 octanol/water partition coefficient is one of the most frequently used descriptors in biological quantitative structure activity relationships. It is considered to reflect the hydrophobicity of a molecule and therefore to be relevant both for correlating the transport properties and the receptor binding of biologically active molecules. Since pharmacological and toxicological research often concerns poorly characterized or not yet synthesized molecules, there is a... 

Environmental impact may occur upon interactions of chemicals with their environmental counterparts due to intermolecular forces the resulting effects depend on the structure and conformation of both reactants. Quantitative structure-activity relationships (QSARs) are used to recognize and utilize the systematic relationships between the principal properties of the chemicals and their biological, ecotoxicological and pharmacological activity. The principle of QSARs consists of relating the activities observed for a series of chemicals to a set of theoretical parameters, which are assumed to describe the relevant properties of their structures quantitatively. Derivation and application of QSARs hence requires three essential prerequisites ... 

From the examination of structure-activity relationships, it has been concluded that a phenyl moiety at C-6 as well as a 4-hydroxypiperidine side-chain attached to C-3 of the pyridazine system is essential for anticonvulsant activity in this class of compounds [184], Compounds (54) and (55) have been found to have similar anticonvulsant profiles in animals (mice, rats and baboons) [165, and literature cited therein] and to represent potent broad-spectrum antiepileptic drugs. Their potency with regard to antagonizing seizures (induced by electro-shock or various chemicals) has been compared with standard anticonvulsants like carbamazepine and phenobarbitone [185, 186], A quantitative electroencephalographic analysis of (55) has been published [187]. From in vitro studies it has been concluded that the anticonvulsant activities of these compounds are not mediated by an enhancement of GABAergic transmission or by an interaction with benzodiazepine receptor sites [ 165,186,187], On the other hand, in vivo experiments showed that (54), at anticonvulsant doses, increases the affinity of flunitrazepam for its central receptor site [ 186], Investigations of (54) and (55) in a behavioural test predictive of antianxiety activity revealed a marked difference in the pharmacological profiles of these structurally closely related compounds the dichloro compound SR 41378 (55) has also been found to possess anxiolytic (anticonflict) properties [165],... 

The cause of the cell cycle specificity of the bisindole alkaloids may be associated with the ability of these compounds to interact with the protein tubulin and thereby inhibit the polymerization (and depolymerization) of microtubules (16,17). In this respect the cellular pharmacology of vinca alkaloids is similar to that of other cytotoxic natural products such as colchicine or podophyllotoxin. On closer inspection, however, Wilson determined that the specific binding site on tubulin occupied by vinblastine or vincristine is chemically distinct from the site occupied by the other natural products (18). Subsequent experiments have determined that the maytansinoids, a class of ansa-macrocycles structurally distinct from the bisindoles, may bind to tubulin at an adjacent (or overlapping) site (19). A partial correlation of the antimitotic activity of these compounds with their tubulin binding properties has been made, but discrepancies in cellular uptake probably preclude any quantitative relationship of these effects (20). 

The lead optimization process is highly iterative, multiparametric, and intensely interdisciplinary. Both qualitative and quantitative information is routinely obtained on analog series of compounds to correlate changes in chemical structure to biological and pharmacological data. The resulting quantitative information provides the basis for the comparison of lead compounds and the ability to establish structure activity relationships (SAR). This multistep evaluation and optimization of ADME-PK properties continues until a defined drug profile is achieved. 

A novel approach to this problem suggested itself from our work on hydrolysis of S-bound sulfoxide. The unique properties of DMSO in its pharmacological actions, such as membrane transport and membrane penetration, are well known (41) and the water-solubilising properties in its metal complexes was readily apparent from the good aqueous solubility of the M-DMSO species. Further, the lability seemed qualitatively of the order of halide (a point confirmed quantitatively during the course of these experiments (23)) and these observations prompted us to probe the following structure-activity relationship ... 

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