Muscarinic acetylcholine receptors: mutant mice provide new insights for drug development

Wess, Jürgen; Eglen, Richard M.; Gautam, Dinesh

doi:10.1038/nrd2379

Cited by 540 publications

(483 citation statements)

References 123 publications

Supporting

Mentioning

471

Contrasting

Unclassified

Order By: Relevance

“…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: 89%

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

Laurino

Matucci

Vistoli

et al. 2016

European Journal of Pharmacology

View full text Add to dashboard Cite

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.

show abstract

Section: Discussionmentioning

confidence: 89%

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

Laurino

Matucci

Vistoli

et al. 2016

European Journal of Pharmacology

View full text Add to dashboard Cite

show abstract

“…Studies have shown that nicotinic receptor agonists, such as epibatidine and nicotine itself, are analgesic when administered centrally (Jones and Dunlop, 2007). Muscarinic receptor agonists such as vendacycline, oxotremorine, CMI-936 and CMI-1145, have also shown potent analgesic action (Tata, 2008;Wess et al, 2007). Furthermore, neostigmine, which inhibits the degradation of acetylcholine, reversed allodynia and hyperalgesia in rat models of neuropathic pain (Jones and Dunlop, 2007).…”

Section: Neurotransmitters and Receptors In Pain And Cognitionmentioning

confidence: 99%

The effect of pain on cognitive function: A review of clinical and preclinical research

Moriarty

McGuire

Finn

2011

Progress in Neurobiology

849

710

View full text Add to dashboard Cite

Cognitive impairment is commonly associated with the pain experience. This impairment represents a major obstacle to daily activities and rehabilitation, especially in the chronic pain population. Here we review clinical and preclinical studies that have investigated pain-related alterations in cognition. These include impaired attentional, executive and general cognitive functioning. We describe the anatomical, neurochemical and molecular substrates common to both cognitive processing and supraspinal pain processing, and present the evidence for their involvement in pain-related cognitive impairment. We also examine the added complexity of cognitive impairment caused by analgesic medications and how this can further impact on morbidity in chronic pain patients. The need for a better understanding of the mechanisms of both pain-induced and treatment-related cognitive impairment is highlighted. Further research in this area will aid our understanding of patient symptoms and their underlying pathophysiology, ultimately leading to increased provision of guided therapy.

show abstract

“…The five muscarinic acetylcholine receptors (mAChRs) have been implicated in numerous diseases, including neurodegenerative and psychiatric disorders (Wess et al, 2007). In particular, the M 1 and M 4 mAChRs have been associated with neurological illnesses, as they are widely expressed throughout the central nervous system (Bymaster et al, 2003;Wess et al, 2003) and are involved in cognitive processes such as attention, learning, and memory (Hasselmo, 2006;Hasselmo and Giocomo, 2006); drugs that selectively target these receptors may thus be useful in the treatment of diseases such as Alzheimer's disease and schizophrenia, in which cognitive processes are disturbed.…”

Section: Introductionmentioning

confidence: 99%

Molecular Mechanisms of Action and In Vivo Validation of an M4 Muscarinic Acetylcholine Receptor Allosteric Modulator with Potential Antipsychotic Properties

Leach

Loiacono

Felder

et al. 2009

Neuropsychopharmacol

143

169

View full text Add to dashboard Cite

We recently identified LY2033298 as a novel allosteric potentiator of acetylcholine (ACh) at the M 4 muscarinic acetylcholine receptor (mAChR). This study characterized the molecular mode of action of this modulator in both recombinant and native systems. Radioligandbinding studies revealed that LY2033298 displayed a preference for the active state of the M 4 mAChR, manifested as a potentiation in the binding affinity of ACh (but not antagonists) and an increase in the proportion of high-affinity agonist-receptor complexes. This property accounted for the robust allosteric agonism displayed by the modulator in recombinant cells in assays of [ 35 S]GTPgS binding, extracellular regulated kinase 1/2 phosphorylation, glycogen synthase kinase 3b phosphorylation, and receptor internalization. We also found that the extent of modulation by LY2033298 differed depending on the signaling pathway, indicating that LY2033298 engenders functional selectivity in the actions of ACh. This property was retained in NG108-15 cells, which natively express rodent M 4 mAChRs. Functional interaction studies between LY2033298 and various orthosteric and allosteric ligands revealed that its site of action overlaps with the allosteric site used by prototypical mAChR modulators. Importantly, LY2033298 reduced [ 3 H]ACh release from rat striatal slices, indicating retention of its ability to allosterically potentiate endogenous ACh in situ. Moreover, its ability to potentiate oxotremorine-mediated inhibition of condition avoidance responding in rodents was significantly attenuated in M 4 mAChR knockout mice, validating the M 4 mAChR as a key target of action of this novel allosteric ligand.

show abstract

Muscarinic acetylcholine receptors: mutant mice provide new insights for drug development

Cited by 540 publications

References 123 publications

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

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

The effect of pain on cognitive function: A review of clinical and preclinical research

Molecular Mechanisms of Action and In Vivo Validation of an M4 Muscarinic Acetylcholine Receptor Allosteric Modulator with Potential Antipsychotic Properties

Contact Info

Product

Resources

About