The Concise Guide to PHARMACOLOGY 2023/24: Introduction and Other Protein Targets

Background and PurposeCurrent pharmacotherapies for Tourette syndrome (TS) are often unsatisfactory and poorly tolerated, underscoring the need for novel treatments. Insufficient striatal acetylcholine has been suggested to contribute to tic ontogeny. Thus, we tested whether activating M1 and/or M4 receptors—the two most abundant muscarinic receptors in the striatum—reduced tic‐related behaviours in mouse models of TS.Experimental ApproachStudies were conducted using CIN‐d and D1CT‐7 mice, two TS models characterized by early‐life depletion of striatal cholinergic interneurons and cortical neuropotentiation, respectively. First, we tested the effects of systemic and intrastriatal xanomeline, a selective M1/M4 receptor agonist, on tic‐like and other TS‐related responses. Then, we examined whether xanomeline effects were reduced by either M1 or M4 antagonists or mimicked by the M1/M3 agonist cevimeline or the M4 positive allosteric modulator (PAM) VU0467154. Finally, we measured striatal levels of M1 and M4 receptors and assessed the impact of VU0461754 on the striatal expression of the neural marker activity c‐Fos.Key ResultsSystemic and intrastriatal xanomeline reduced TS‐related behaviours in CIN‐d and D1CT‐7 mice. Most effects were blocked by M4, but not M1, receptor antagonists. VU0467154, but not cevimeline, elicited xanomeline‐like ameliorative effects in both models. M4, but not M1, receptors were down‐regulated in the striatum of CIN‐d mice. Additionally, VU0467154 reduced striatal c‐Fos levels in these animals.Conclusion and ImplicationsActivation of striatal M4, but not M1, receptors reduced tic‐like manifestations in mouse models, pointing to xanomeline and M4 PAMs as novel putative therapeutic strategies for TS.

Section: Nomenclature Of Targets and Ligandsmentioning

confidence: 99%

Activation of M₄ muscarinic receptors in the striatum reduces tic‐like behaviours in two distinct murine models of Tourette syndrome

Cadeddu,

Braccagni,

Branca

et al. 2024

“…Key protein targets and ligands in this article are hyperlinked to corresponding entries in https://www.guidetopharmacology.org and are permanently archived in the Concise Guide to PHARMACOLOGY 2023/24 (Alexander et al, 2023).…”

Section: Nomenclature Of Targets and Ligandsmentioning

confidence: 99%

A novel ryanodine receptor 2 inhibitor, M201‐A, enhances natriuresis, renal function and lusi‐inotropic actions: Preclinical and phase I study

Kaneko,

Loughrey,

Smith

et al. 2024

Background and PurposeThe ryanodine receptor 2 (RyR2) is present in both the heart and kidneys, and plays a crucial role in maintaining intracellular Ca2+ homeostasis in cells in these organs. This study aimed to investigate the impact of M201‐A on RyR2, as well as studying its effects on cardiac and renal functions in preclinical and clinical studies.Experimental ApproachFollowing the administration of M201‐A (1,4‐benzothiazepine‐1‐oxide derivative), we monitored diastolic Ca2+ leak via RyR2 and intracellular Ca2+ concentration in isolated rat cardiomyocytes and in cardiac and renal function in animals. In a clinical study, M201‐A was administered intravenously at doses of 0.2 and 0.4 mg·kg−1 once daily for 20 min for four consecutive days in healthy males, with the assessment of haemodynamic responses.Key ResultsIn rat heart cells, M201‐A effectively inhibited spontaneous diastolic Ca2+ leakage through RyR2 and exhibited positive lusi‐inotropic effects on the rat heart. Additionally, it enhanced natriuresis and improved renal function in dogs. In human clinical studies, when administered intravenously, M201‐A demonstrated an increase in natriuresis, glomerular filtration rate and creatinine clearance, while maintaining acceptable levels of drug safety and tolerability.Conclusions and ImplicationsThe novel drug M201‐A inhibited diastolic Ca2+ leak via RyR2, improved cardiac lusi‐inotropic effects in rats, and enhanced natriuresis and renal function in humans. These findings suggest that this drug may offer a potential new treatment option for chronic kidney disease and heart failure.

“…The group size in this study is the number of independent values (not technical replicates), and that statistical analysis was done using these independent values. Data and statistical analyses comply with the recommendations of the British Journal of Pharmacology on experimental design and analysis(Curtis et al, 2022).2.16 | Nomenclature of Targets and LigandsKey protein targets and ligands in this article are hyperlinked to corresponding entries in https://www.guidetopharmacology.org, and are permanently archived in the Concise Guide to PHARMACOLOGY 2023/24(Alexander et al, 2023).…”

mentioning

confidence: 99%

Daidzein ameliorates nonmotor symptoms of manganese‐induced Parkinsonism in zebrafish model: Behavioural and biochemical approach

Haridevamuthu,

Sudhakaran,

Pachaiappan

et al. 2024

Background and PurposeParkinson's disease (PD) is a prevalent neurodegenerative movement disorder characterized by motor dysfunction. Environmental factors, especially manganese (Mn), contribute significantly to PD. Existing therapies are focused on motor coordination, whereas nonmotor features such as neuropsychiatric symptoms are often neglected. Daidzein (DZ), a phytoestrogen, has piqued interest due to its antioxidant, anti‐inflammatory, and anxiolytic properties. Therefore, we anticipate that DZ might be an effective drug to alleviate the nonmotor symptoms of Mn‐induced Parkinsonism.Experimental ApproachNaïve zebrafish were exposed to 2 mM of Mn for 21 days and intervened with DZ. Nonmotor symptoms such as anxiety, social behaviour, and olfactory function were assessed. Acetylcholinesterase (AChE) activity and antioxidant enzyme status were measured from brain tissue through biochemical assays. Dopamine levels and histology were performed to elucidate neuroprotective mechanism of DZ.Key ResultsDZ exhibited anxiolytic effects in a novel environment and also improved intra and inter fish social behaviour. DZ improved the olfactory function and response to amino acid stimuli in Mn‐induced Parkinsonism. DZ reduced brain oxidative stress and AChE activity and prevented neuronal damage. DZ increased DA level in the brain, collectively contributing to neuroprotection.Conclusion and ImplicationsDZ demonstrated a promising effect on alleviating nonmotor symptoms such as anxiety and olfactory dysfunction, through the mitigation of cellular damage. These findings underscore the therapeutic potential of DZ in addressing nonmotor neurotoxicity induced by heavy metals, particularly in the context of Mn‐induced Parkinsonism.