The focus of this R21 application is novel lead molecule optimization through structure-guided, computer-aided synthetic medicinal chemistry approaches. Our target is the neuronal nicotinic acetylcholine receptor (nAChR). Structure-based drug design as a """"""""rational"""""""" method has been quite successful, contributing to the introduction of ~50 compounds into clinical trials and to numerous drug approvals. nAChRs and their many subtypes are linked to a number of neurological diseases such as schizophrenia, attention deficit hyperactivity disorder, Alzheimer's disease, Tourette's syndrome, Parkinson's disease, autism, and some types of epilepsy. In addition nicotine is one of the most heavily used addictive drugs in the United States. Considering 1) their physisological/pathophysiological importance, 2) the time and effort (and resources) devoted to drug discovery in this area over the past twenty years, 3) most drug discovery programs in this area targeting orthosteric sites [endogenous agonist (acetylcholine) binding sites], and 4) few drugs that are selectively targeting specific subtypes of nAChRs being identified, new approaches in the area of nAChR drug discovery need to be pursued. For the past several years our laboratories have investigated a novel class of molecules that act as negative allosteric modulators. Using computational approaches we have recently identified a novel site on nAChR where these molecules likely bind. Most recently we have identified a novel lead molecule that selectively inhibits 42 nAChRs. The importance of this discovery is that this molecule was identified via molecular dynamics simulation and virtual screening using our computational model of the allosteric site on human 42 nAChRs, thus validating our model and supporting our proposed approaches. Our hypothesis is that molecular characterization and computational modeling of these allosteric sites on specific subtypes of nAChRs will lead to the discovery of molecules that target specific subtypes of nAChRs. Our contention is that greater structural diversity exists in allosteric sites than in orthosteric sites and, once these sites are identified and characterized, the development of nAChR subtype-selective agents will follow. As proof of concept, this R21 proposal focuses on a negative allosteric binding site on human 42 nAChRs and the discovery of drugs that selectively bind this site (negative allosteric modulators, NAMs). Our goals are 1) to characterize the allosteric binding sites on human 42 nAChRs and 2) to improve the potency and selectivity of our lead molecule through combined computational and synthetic medicinal chemistry approaches. Success will be defined as a) selectivity toward 42 nAChRs of 1000 fold, and b) a 100- to 1000-fold increase in potency.
Historically, receptors were identified through the use of specific drugs that altered functional processes mediated by these receptors. From Sir Henry Dale's work with muscarine and nicotine to R.P. Ahlquist's sub- classification of adrenergic receptors, pharmacological identification was the norm. These approaches led 1) to the discovery of the physiological importance of specific receptors, 2) to the identification of new therapeutic targets, and 3) to novel strategies that treat disease. Over the past 25 to 30 years, molecular biological approaches have now identified a host of new receptors and new receptor subtypes. Since these approaches are not linked to receptor-specific drugs, the shear numbers of new receptor subtypes have outstretched the availability of receptor-specific drugs. Nicotinic receptors and their many subtypes are linked to a number of neurological diseases such as schizophrenia, attention deficit hyperactivity disorder, Alzheimer's disease, Tourette's syndrome, Parkinson's disease, autism, and some types of epilepsy. In addition, nicotine is one of the most heavily used and addictive drugs in the United States;it is estimated that 70 million people 12 and older (or 29 percent of the U.S. population) use cigarettes, cigars and or chewing tobacco products, resulting in ~ 440,000 premature deaths each year with an annual cost of more than $75 billion in direct medical charges. Taking into consideration the importance of these receptors as well as considering the time and effort (and resources) devoted to the discovery of selective molecules over the past twenty years, few drugs that target specific subtypes of nicotinic receptors have been identified. New approaches in the area of nicotinic receptor drug discovery need to be pursued. Our novel target (an allosteric site recently identified by our laboratory), our promising lead molecule (recently identified via virtual screening), and our rational drug design approach (involving computer-aided drug design), provide a promising approach for the discovery of molecules that selectively target specific subtypes of nicotinic receptors.
