Muscarinic acetylcholine receptors: novel opportunities for drug development

Kruse, Andrew C.; Kobilka, Brian K.; Gautam, Dinesh; Sexton, Patrick M.; Christopoulos, Arthur; Wess, Jürgen

doi:10.1038/nrd4295

Cited by 374 publications

(368 citation statements)

References 120 publications

(146 reference statements)

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“…Although direct anatomic evidence for the presence of M 5 receptors in DA axons is lacking, functional studies implicate M 5 mAChRs in either facilitating (8,10) or depressing (11) DA release. In the past, studies in this field have been hampered by the lack of selective muscarinic agonists and antagonists (18). To overcome this limitation, this study takes advantage of mutant mouse lines carrying genetic deletions of selected mAChR subtypes (19) to determine their specific role in modulating DA transmission in the striatum.…”

mentioning

confidence: 99%

Muscarinic regulation of dopamine and glutamate transmission in the nucleus accumbens

Shin

Adrover

Wess

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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108

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Cholinergic transmission in the striatum functions as a key modulator of dopamine (DA) transmission and synaptic plasticity, both of which are required for reward and motor learning. Acetylcholine (ACh) can elicit striatal DA release through activation of nicotinic ACh receptors (nAChRs) on DA axonal projections. However, it remains controversial how muscarinic ACh receptors (mAChRs) modulate striatal DA release, with studies reporting both potentiation and depression of striatal DA transmission by mAChR agonists. This study investigates the mAChR-mediated regulation of release from three types of midbrain neurons that project to striatum: DA, DA/glutamate, and glutamate neurons. We found that M5 mAChRs potentiate DA and glutamate release only from DA and DA/glutamate projections from the midbrain. We also show that M2/M4 mAChRs depress the nAChR-dependent mechanism of DA release in the striatum. These results suggest that M5 receptors on DA neuron terminals enhance DA release, whereas M2/M4 autoreceptors on cholinergic terminals inhibit ACh release and subsequent nAChR-dependent DA release. Our findings clarify the mechanisms of mAChR-dependent modulation of DA and glutamate transmission in the striatum.

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mentioning

confidence: 99%

Muscarinic regulation of dopamine and glutamate transmission in the nucleus accumbens

Shin

Adrover

Wess

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

108

100

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“…In fact, while the -phenylethyl moiety was recognized essential for interacting at adrenergic receptors, the diphenoxyl and iodide ion residues are here identified as crucial for establishing chemical connections with strategic amino acid residues in the active site of the muscarinic type 3 receptor which is however conserved among receptor subtypes and among species (Kruse et al, 2014).…”

Section: Discussionmentioning

confidence: 88%

“…In fact, even if T1AM shows the lowest affinity for the type 2 than for the other subtypes, the differences among pKi values calculated from binding studies are not so high to consider the ligand as "selective" for one specific muscarinic subtype. This is not surprising since T1AM is an endogenous compound and because the amino acids lining the orthosteric binding site for muscarinic ligands are highly conserved among the five muscarinic subtypes (Wess et al, 2007) (Kruse et al, 2014). This finding does not exclude that T1AM skeleton might serve to develop novel small-molecule orthosteric ligands endowed with a high degree of selectivity for individual muscarinic subtypes, a goal which remains a major challenge for medicinal chemists.…”

Section: Discussionmentioning

confidence: 99%

3-iodothyronamine (T1AM), a novel antagonist of muscarinic receptors

Laurino

Matucci

Vistoli

et al. 2016

European Journal of Pharmacology

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Abstract3-iodothyronamine (T1AM) is a trace amine suspected to derive from thyroid hormone metabolism. T1AM was described as a ligand of G-protein coupled monoaminergic receptors, including trace amine associated receptors, suggesting the amine may exert a modulatory role on the monoaminergic transmission. Nothing is known on the possibility that T1AM could also modulate the cholinergic transmission interacting with muscarinic receptors.We evaluated whether T1AM (10 nM-100 M) was able to i) displace T1AM recognized all muscarinic receptor subtypes (pKi values in the micromolar range). Interacting at type 3, T1AM reduced acetylcholine-increased pERK 1/2 levels. T1AM reduced carbachol-induced contraction of the rat urinary bladder. The fenoxyl residue and the iodide ion were found essential for establishing contacts with the active site of the rat muscarinic type 3 receptor subtype.Our results indicate that T1AM binds at muscarinic receptors behaving as a weak, not selective, antagonist. This finding adds knowledge on the pharmacodynamics features of T1AM and it may prompt investigation on novel pharmacological effects of T1AM at 3 conditions of hyper-activation of the muscarinic tone including the overactive urinary bladder.

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“…Discussion mAChRs are involved in some of the most debilitating diseases, both centrally-such as Parkinson's disease, Alzheimer's disease, and schizophrenia-and peripherally, such as asthma and heart dysfunctions (40). Although, several orthosteric cholinergic drugs have made their way to the market, all of them exhibit side effects.…”

Section: Subtype Selectivity Of Modulators On Agonist-mediated Responmentioning

confidence: 99%

Accelerated structure-based design of chemically diverse allosteric modulators of a muscarinic G protein-coupled receptor

Miao

Goldfeld

Moo

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Design of ligands that provide receptor selectivity has emerged as a new paradigm for drug discovery of G protein-coupled receptors, and may, for certain families of receptors, only be achieved via identification of chemically diverse allosteric modulators. Here, the extracellular vestibule of the M 2 muscarinic acetylcholine receptor (mAChR) is targeted for structure-based design of allosteric modulators. Accelerated molecular dynamics (aMD) simulations were performed to construct structural ensembles that account for the receptor flexibility. Compounds obtained from the National Cancer Institute (NCI) were docked to the receptor ensembles. Retrospective docking of known ligands showed that combining aMD simulations with Glide induced fit docking (IFD) provided much-improved enrichment factors, compared with the Glide virtual screening workflow. Glide IFD was thus applied in receptor ensemble docking, and 38 top-ranked NCI compounds were selected for experimental testing. In [ 3 H]Nmethylscopolamine radioligand dissociation assays, approximately half of the 38 lead compounds altered the radioligand dissociation rate, a hallmark of allosteric behavior. In further competition binding experiments, we identified 12 compounds with affinity of ≤30 μM. With final functional experiments on six selected compounds, we confirmed four of them as new negative allosteric modulators (NAMs) and one as positive allosteric modulator of agonist-mediated response at the M 2 mAChR. Two of the NAMs showed subtype selectivity without significant effect at the M 1 and M 3 mAChRs. This study demonstrates an unprecedented successful structure-based approach to identify chemically diverse and selective GPCR allosteric modulators with outstanding potential for further structure-activity relationship studies.GPCR | allosteric modulators | ensemble docking | affinity | cooperativity

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Muscarinic acetylcholine receptors: novel opportunities for drug development

Cited by 374 publications

References 120 publications

Muscarinic regulation of dopamine and glutamate transmission in the nucleus accumbens

Muscarinic regulation of dopamine and glutamate transmission in the nucleus accumbens

3-iodothyronamine (T1AM), a novel antagonist of muscarinic receptors

Accelerated structure-based design of chemically diverse allosteric modulators of a muscarinic G protein-coupled receptor

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