Brain Neuronal Nicotinic Receptors as New Targets for Drug Discovery

Abstract

Neuronal nicotinic receptors (nAChRs) are a heterogeneous family of ion channels differently expressed in the nervous system where, by responding to the endogenous neurotransmitter acetylcholine, they contribute to a wide range of brain activities and influence a number of physiological functions. Over recent years, the application of newly developed molecular and cellular biological techniques has made it possible to correlate the subunit composition of nAChRs with specific nicotine-elicited behaviours, and refine some of the in vivo physiological functions of nAChR subtypes. The major new findings are the widespread expression of nAChRs, outside the nervous system, their specific and complex organisation, and their relevance to normal brain function. Moreover, the combination of clinical and basic research has better defined the involvement of nAChRs in a growing number of nervous pathologies other than degenerative diseases. However, there are still only a limited number of nicotinic-specific drugs and, although some nicotinic agonists have an interesting pharmacology, their clinical use is limited by undesirable side effects. Some selective nicotinic ligands have recently been developed and used to explore the complexity of nAChR subtype structure and function in the expectation that they will become rational therapeutic alternatives in a number of neurodegenerative, neuropsychiatric and neurological disorders. In this review, we will discuss the molecular basis of brain nAChR structural and functional diversity mainly in pharmacological and biochemical terms, and summarise current knowledge concerning the newly discovered drugs used to classify the numerous receptor subtypes and treat the brain diseases in which nAChRs are involved.

Nicotinic receptors as CNS targets for Parkinson's disease

“…There is a requirement for α subunits in the receptor complex, as these possess the recognition site for acetylcholine. The β subunit does not bind acetylcholine, however it modulates the interaction of the ligand with the α subunit, thereby affecting the physiological and pharmacological properties of the receptor [67][68][69][70][71]. Multiple nAChR subtypes ( Fig.…”

“…NAChRs are pentameric ligand gated ion channels comprised of different combinations of α and β subunits to form heteromeric receptors, and select α subunits to form homomeric receptors [67][68][69][70][71]. There is a requirement for α subunits in the receptor complex, as these possess the recognition site for acetylcholine.…”

Structure and Activity of α-Conotoxin PeIA at Nicotinic Acetylcholine Receptor Subtypes and GABAB Receptor-coupled N-type Calcium Channels

“…Specific subtypes have different expression patterns and pharmacological and biophysical profiles. Targeting individual subtypes can potentially result in drug leads with minimal side effects (10,11). For example, the ␣9␣10 nAChR subtype has been proposed as a potential target for pain relief (12,13).…”

Continuous and Intermittent Nicotine Treatment Reduces l-3,4-Dihydroxyphenylalanine (l-DOPA)-Induced Dyskinesias in a Rat Model of Parkinson's Disease

“…One drug that has recently been shown to attenuate L-DOPA-induced dyskinetic-like movements in nonhuman primates is nicotine (Quik et al, 2007b). Nicotine may exert this effect by acting on nicotinic acetylcholine receptors, which are present on dopaminergic terminals in the striatum and involved in regulating dopamine release (Gotti et al, 2006;Grady et al, 2007;Quik et al, 2007a). Nicotine reduces L-DOPA-induced dyskinetic-like movements in both L-DOPA naive and L-DOPA-primed monkeys when administered via the drinking water.…”