BC(DEF) Coordinates 5. Shape‐Specific vs. Orientation‐Averaged Interactions of Neuroleptics and Other Centrally Acting Drugs: Correlation of Effects in Five in vitro Test Systems

Abstract

AbstractTo evaluate further a methodology proposed for determining whether the pharmacological actions of compounds are due to shape‐specific or orientation‐averaged molecular interactions with biological systems, the activities of neuroleptics and other centrally acting drugs in five in vitro test systems were correlated with the compounds' BCDEF coordinates. It is hypothesized that shape‐specific interactions will tend to enhance the activity of a compound in the test system and, thus, these compounds would be the positive outliers in such an analysis. These compounds were floated and the correlation repeated until all of the specifically‐acting compounds were identified. Inhibition of [3H]haloperidol, [3H]flupenthixol, and [3H]dopamine binding by neuroleptics and catecholamines appeared to be primarily due to shape‐specific molecular interactions with the receptor. In contrast, neuroleptic‐induced inhibition of synaptosomal GABA accumulation and of calmodulin‐mediated phosphodiesterase activity appeared to be due to non‐specific interactions, that is, these effects could be explained exclusively by the same orientation‐averaged interactions that determine the overall physicochemical properties of the test molecules. Although lipophilic in character, non‐specific interactions with these biological test systems are less selective against bulky and polar molecules than are common models of lipophilicity such as partitioning between water and immiscible organic solvents.