TY - JOUR

T1 - Targeting α4β2 nAChRs in CNS disorders: Perspectives on positive allosteric modulation as a therapeutic approach

AU - Grupe, Morten

AU - Grunnet, Morten

AU - Bastlund, Jesper F.

AU - Jensen, Anders A.

PY - 2015

Y1 - 2015

N2 - The nicotinic acetylcholine receptors (nAChRs) are ligand-gated ion channels broadly involved in regulating neurotransmission in the central nervous system (CNS) by conducting cation currents through the membrane of neurons. Many different nAChR subtypes exist with each their functional characteristics, expression pattern and pharmacological profile. The focus of the present MiniReview is on the heteromeric α4β2 nAChR, as activity at this subtype contributes to cognitive functioning through interactions with multiple neurotransmitter systems and is implicated in various CNS disorders, for example schizophrenia and Alzheimer's disease. Additionally, the α4β2 nAChR provides an extra layer of molecular complexity by existing in two different stoichiometries determined by the subunit composition. Such findings have founded the rationale that pharmacological modulation of the α4β2 nAChR may be used as a treatment approach in various CNS disorders. As subtype-selective agonists and other cholinergic ligands have only shown limited therapeutic success, the focus of recent drug development endeavours has largely shifted to positive allosteric modulators (PAMs). By potentiating the action of an agonist through binding to an allosteric site, a PAM can enhance cholinergic neurotransmission, thus compensating for compromised neuronal communication in a pathophysiological setting. The pharmacological advantages of PAMs compared to other types of ligands include minimal interference with spatial and temporal aspects of neurotransmission as well as higher subtype selectivity, hypothetically resulting in high clinical efficacy with minimal adverse effects. In this MiniReview, we describe the currently identified compounds, which potentiate the effects of agonists at the α4β2 nAChR. The potential clinical advantages and concerns of PAMs are discussed in the light of the role of α4β2 nAChRs as key regulators of fast synaptic transmission.

AB - The nicotinic acetylcholine receptors (nAChRs) are ligand-gated ion channels broadly involved in regulating neurotransmission in the central nervous system (CNS) by conducting cation currents through the membrane of neurons. Many different nAChR subtypes exist with each their functional characteristics, expression pattern and pharmacological profile. The focus of the present MiniReview is on the heteromeric α4β2 nAChR, as activity at this subtype contributes to cognitive functioning through interactions with multiple neurotransmitter systems and is implicated in various CNS disorders, for example schizophrenia and Alzheimer's disease. Additionally, the α4β2 nAChR provides an extra layer of molecular complexity by existing in two different stoichiometries determined by the subunit composition. Such findings have founded the rationale that pharmacological modulation of the α4β2 nAChR may be used as a treatment approach in various CNS disorders. As subtype-selective agonists and other cholinergic ligands have only shown limited therapeutic success, the focus of recent drug development endeavours has largely shifted to positive allosteric modulators (PAMs). By potentiating the action of an agonist through binding to an allosteric site, a PAM can enhance cholinergic neurotransmission, thus compensating for compromised neuronal communication in a pathophysiological setting. The pharmacological advantages of PAMs compared to other types of ligands include minimal interference with spatial and temporal aspects of neurotransmission as well as higher subtype selectivity, hypothetically resulting in high clinical efficacy with minimal adverse effects. In this MiniReview, we describe the currently identified compounds, which potentiate the effects of agonists at the α4β2 nAChR. The potential clinical advantages and concerns of PAMs are discussed in the light of the role of α4β2 nAChRs as key regulators of fast synaptic transmission.

U2 - 10.1111/bcpt.12361

DO - 10.1111/bcpt.12361

M3 - Journal article

C2 - 25441336

VL - 116

SP - 187

EP - 200

JO - Basic and Clinical Pharmacology and Toxicology

JF - Basic and Clinical Pharmacology and Toxicology

SN - 1742-7835

IS - 3

ER -