Muscarinic and nicotinic acetylcholine receptor agonists and allosteric modulators for the treatment of schizophrenia

Abstract

Muscarinic and nicotinic acetylcholine (ACh) receptors (mAChRs and nAChRs) are emerging as important targets for the development of novel treatments for the symptoms associated with schizophrenia. Preclinical and early proof-of-concept clinical studies have provided strong evidence that activators of specific mAChR (M(1) and M(4)) and nAChR (α(7) and α(2)β(4)) subtypes are effective in animal models of antipsychotic-like activity and/or cognitive enhancement, and in the treatment of positive and cognitive symptoms in patients with schizophrenia. While early attempts to develop selective mAChR and nAChR agonists provided important preliminary findings, these compounds have ultimately failed in clinical development due to a lack of true subtype selectivity and subsequent dose-limiting adverse effects. In recent years, there have been major advances in the discovery of highly selective activators for the different mAChR and nAChR subtypes with suitable properties for optimization as potential candidates for clinical trials. One novel strategy has been to identify ligands that activate a specific receptor subtype through actions at sites that are distinct from the highly conserved ACh-binding site, termed allosteric sites. These allosteric activators, both allosteric agonists and positive allosteric modulators, of mAChR and nAChR subtypes demonstrate unique mechanisms of action and high selectivity in vivo, and may provide innovative treatment strategies for schizophrenia.

Figure 1

Schematic representation of a hypothetical cholinergic synapse illustrating general synaptic localization and function of cholinergic receptors relevant to schizophrenia. mAChR subtypes have diverse synaptic localization patterns and function pre- and postsynaptically to modulate neurotransmitter release and postsynaptic excitability, respectively. For instance, the M₂ and M₄ mAChRs serve as autoreceptors on cholinergic terminals to suppress ACh release and inhibit cholinergic neurotransmission at select synapses in the central nervous system (left neuron). The mAChRs located on non-cholinergic neurons act as heteroceptors controlling the release of other neurotransmitters, such as DA (not shown). M₁, M₃, M₅, but also M₄ mAChRs that are located postsynaptically facilitate slow cholinergic synaptic neurotransmission relative to nAChR subtypes. The α₇ and α₄β₂ nAChR subtypes mediate fast synaptic transmission and also use-dependent changes required for neuronal plasticity. These nAChR subtypes can have both pre- and postsynaptic localization. The endogenous ligand of these cholinergic receptors, ACh, is synthesized in cholinergic neurons (left neuron) by the enzyme ChAT through the transfer of acetyl-CoA onto choline. Choline uptake is mediated by presynaptic high-affinity choline transporters (ChT). After synthesis, ACh is packaged into synaptic vesicles by the vesicular ACh transporter (vAChT). After neuronal activation-mediated release into the synaptic cleft, ACh can bind to pre- and postsynaptic receptors, or it can be inactivated through hydrolysis by the AChE enzymes, a process that can be inhibited by different substances (eg, organophosphates, AChE inhibitors) to increase synaptic ACh levels. Once ACh is hydrolyzed, choline is transported through the ChTs into the presynaptic terminal, where it is again synthesized into ACh.

Figure 2

The structure and signaling pathways of mAChRs and nAChRs. Each mAChR subtype is a seven-transmembrane protein, which belongs to two major functional classes based on G-protein coupling. The M₁, M₃, and M₅ mAChRs selectively couple to the Gq/G11-type G-proteins resulting in the generation of inositol-1,4,5-trisphosphate (IP3) and 1,2-diacylglycerol (DAG) through activation of the phosphoinositide-specific phospholipase-Cβ leading to increased intracellular calcium levels. The M₂ and M₄ mAChRs preferentially activate Gi/Go-type G-proteins, thereby inhibiting adenylate cyclase, reducing intracellular concentration of cAMP, and prolonging potassium channel opening. All mAChR subtypes show a high sequence homology across species, particularly in the orthosteric ACh-binding sites. Neuronal nAChRs are pentameric ligand-gated ion channels. The most abundant neuronal subunits are α₄, β₂, and α₇, with the heteromeric α₄β₂ receptor subtype in highest abundance. The heteromeric α₄β₂ receptor subtype can exist in two different forms: (α4)₂(β2)₃ receptors show low Ca²⁺ permeability and high affinity to ACh and nicotine, whereas (α4)₃(β2)₂ receptors have high Ca²⁺ permeability. By contrast, the α₇ nAChR also shows high permeability to Ca²⁺ relative to the heteromeric α₄β₂ nAChRs. The action of α₄β₂ nAChRs can enhance intracellular levels of Ca²⁺ by secondary activation of VOCCs, whereas α₇ nAChRs preferentially increase Ca²⁺ release from ryanodine-sensitive intercellular stores through CICR. The capacity of these different nAChR subtypes to couple to VOCC or CICR mechanisms results in distinct patterns of Ca²⁺ signaling that can provide a broader control of synaptic plasticity and neurotransmitter release, as well as gene transcription.