Studies on the relationship of binding affinity to psychoactive and anticholingergic potency of a group of psychotomimetic glycolates

Abstract

A study was undertaken of the possible relationship of the binding affinity of a series of anticholinergic psychotomimetic drugs to their psychopharmacological and anticholinergic effects. Binding was measured to brain homogenates and nerve endings using [3H]quinuclidinyl benzilate (QB), a highly potent psychotomimetic agent presumably affecting muscarinic sites in the brain. The two stereoisomers of QB were compared; and although the L-isomer had 15 times the binding affinity of D-isomer, the L-isomer had over 200 times the psychopharmacological potency of the D-form. When the relative binding affinity of a homologous series of glycolate esters was compared with their relative psychoacitve potency, the correlation was excellent; however, when compounds with heterocyclic amino rings (e.g., tropanol) other than quinuclidine and piperidine were considered, the correlation was poor. The correlation between binding affinity and antagonism to acetylcholine-induced contraction of ileum was more consistent. A study was undertaken on the effect of added lipids on QB binding to nerve endings, and it was found that phosphatidyl serine had a significant enhancing effect while gangliosides were inhibitory.