Ion Channel Blockers and Nicotinic Agonists and Antagonists to Probe Brain Nicotinic Receptors

In an effort to investigate the nature of brain nicotinic receptors receptor binding studies have been undertaken using nicotinic radioligands. With 3H-nicotine or the 3H-azetidine analogue of nicotine the Scatchard plot yielded a high and lower affinity site; whereas, with 3H-methylcarbamylcholine (3H-MCC) only the lower affinity site was observed. Based on the observation that the addition of a methyl group on carbamylcholine yielded a potent and specific nicotinic agonist, a number of nicotinic agonists and antagonists have been synthesized and their structure-activity relationships described. Studies are described using 3H-mecamylamine as a ligand for investigating the ion channel associated with brain nicotinic receptors. A good correlation was observed between the Ki values of a variety of mecamylamine and pempidinge analogues and their ability to antagonize the psychotropic effects of nicotine. Since nicotine competed for 3H-mecamylamine binding, it was inferred that nicotine may be interacting with the ion channel as well as with the recognition site.