Structure-activity relationships of a number of synthetic cocaine analogs are described comparing their effectiveness in antagonizing the behavioral effects of nicotine in mice with their ability to compete for [3H]mecamylamine, [3H]nicotine, and [3H]3-quinuclidinylbenzilate ([3H]QNB) binding to calf brain membranes. Within a series of phenyltropane carboxylic acid methyl esters the most potent analogues were the 4-I and 4-F-phenyl analogs, while replacement of F by Cl or alkyl groups diminished potency. The isopropyl and phenylcarboxylic acid esters were comparable in potency to the methyl esters. There appeared to be a relationship between the potency of the analogs in inhibiting the dopamine transporter and nicotine antagonism. A good correlation was observed between pharmacologic potency and [3H]mecamylamine binding to brain membranes. It was concluded that the antagonistic action of the cocaine analogs involved an ion channel site on the neuronal nicotinic cholinergic receptors.
Animals Brain