Structure-activity relationships drug-receptor interactions

Weinstein, H., R. Osman, and J. P. Green. 1979. The Molecular Basis of Structure-Activity Relationships Quantum Chemical Recognition Mechanisms in Drug-Receptor Interactions. In Computer-Assisted Drug Design. E. C. Olson and R. E. Christofferson, eds. American Chemical Society, Washington, D.C. 

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 PE spectra of some other alkaloids like methadone and the opiate narcotics morphine, codeine and heroin have been investigated by Klasinc and coworkers95. Also in this study structure-activity relationships based on IPs were sought but not found. Since the interaction of the drug molecule with the receptor is highly specific, it is not unreasonable that the molecular rather than the electronic structure is more important for the physiological activity. 

KARMA is an interactive computer assisted drug design tool that incorporates quantitative structure-activity relationships (QSAR), conformational analysis, and three-dimensional graphics. It represents a novel approach to receptor mapping analysis when the x-ray structure of the receptor site is not known, karma utilizes real time interactive three-dimensional color computer graphics combined with numerical computations and symbolic manipulation techniques from the field of artificial intelligence. 

Elucidation of the structural requirements for drug interaction at the recognition site is by the study of structure-activity relationships (SAR), in which, according to a specific biologic response, the effects of systematic molecular modification of a parent drug structure are determined. Such studies have permitted the classification of discrete classes of pharmacological receptors. 

Thus, in 2- and 3-monomethyl, and 2,5- and 2,3-dimethyl derivatives with preferred equatorial hydrocarbon substituents, consistent and additive stereochemical structure-activity relationships are found. Furthermore, the more active antipodal forms have potencies close to that of the desmethyl parent ester, in support of an essentially passive role for methyl substituents of this type in the drug-receptor interactions. 

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