Drug-receptor quantitative analysis

Wieland GA, Molinoff PB. 1981. Quantitative analysis of drug-receptor interactions I. Determination of kinetic and equilibrium properties. Life Sci 29 313. 

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. 

Molecules of similar biochemical activity often show common 3D shape features. Consequently, the characterization of the shapes of formal molecular bodies and the recognition, description, and, ultimately, the numerical evaluation of similarity among molecules are of major importance in modern pharmaceutical research, as well as in pesticide and herbicide chemistry. The analysis of molecular shape is an important component of research aimed at the elucidation of drug-receptor interactions and in studies of quantitative structure-activity relationships in contemporary drug design. 

Drug-receptor interactions may quantitatively differ among rapidly converting multiple receptor states that are induced by agonist binding. While most studies commonly focus on analysis of ligand-receptor interactions and cellular responses under presumed steady-state conditions, experimental techniques available for the quantitative analysis of drug-receptor interactions with transient receptor conformational... 

PEPER K., DREYER F. and MOlLER K., Analysis of cooperativity of drug-receptor interaction by quantitative iontophoresis at frog motor end plate. Cold Spring Harbor Symp. Quant. Biol. 40, 187-192, 1975. 

The basic methodical approach in receptor studies is that of quantitative estimations of the relationship between drug concentration and effect evoked, by quantitative analysis of agonist—antagonist interaction and by studying structure-action relationships. 

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],... 

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