The nicotinic acetylcholine receptors (nAChRs) are pentameric ligand-gated excitatory ion channels located in the central nervous system (CNS) and periphery. The nAChRs comrpise various combinations of 1 and 2 subunits that form hetero- or homomeric combinations. The neuronal nAChRs play a role in a number of processes connected to cognitive function, learning and memory, arousal, reward, motor control, and analgesia. Subtype-selective nAChR ligands offer potential for treatment of numerous pathophysiological conditions including drug addiction, pain, epilepsy, and neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease. The pharmacology of these receptors is not yet thoroughly understood. Although extensive series of nAChR ligands have been reported, rational design of subtype-selective agonists and antagonists has been difficult. For the 1324 nAChR in particular, no truly selective ligands are available. This situation can be attributed mainly to inadequate structural information on the receptor subtypes and their binding sites, the high sequence homology among the subunits that form the nAChRs, and a lack of subtype- selective ligands. Photoaffinity labeling (PAL) has been a powerful approach for identifying subunits and mapping the active sites of biopolymers such as DNA and protein molecules, and it enables the direct probing of a target protein through a covalent bond photochemically introduced between a ligand and its specific receptor. Our laboratory has recently identified several potent 1324-selective ligands that have low nanomolar affinity and very high selectivity for 1324 versus 1422 subtype. The high selectivity of these ligands for the 1324 receptor makes them ideal leads for development of tools to define the structural basis of subtype selectivity and to understand the role of 1324 nAChR in conditions in which 1324 nAChR is involved, such as drug addiction. The goal of the research is to develop PAL ligands for the 1324 nAChR subtype. Development of suitable PAL ligands will provide useful tools to elucidate the ligand-receptor interactions and provide information on structure of the receptor and its bioactive pocket.
The specific aims are to use SAR studies and medicinal chemistry to develop potential 1324-selective PAL ligands using our lead compounds as a prototype;use in vitro pharmacology to characterize binding and functional properties of novel ligands;and determine if photoactivation leads to irreversible (wash-resistant) binding and irreversible inhibition of receptor activation.

Public Health Relevance

The 1324 nicotinic acetylcholine receptor (nAChR) has been shown to play a role in drug addiction. However, its biology and pharmacology are not yet thoroughly understood. The basis of subtype selectivity for nAChR ligands is also not well-understood. This proposed project will develop 1324 photoaffinity ligands based on our recently discovered selective and potent lead compounds. These photoaffinity ligands will be useful tools to understand the structural basis of selectivity and rational design of 1324 nAChR for the treatment of drug addiction.

National Institute of Health (NIH)
National Institute on Drug Abuse (NIDA)
Small Research Grants (R03)
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Special Emphasis Panel (ZRG1-MNPS-C (09))
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Hillery, Paul
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Sri International
Menlo Park
United States
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