Expert Opin Investig Drugs
Department of Pharmaceutical Sciences, College of Pharmacy, University of Nebraska Medical Center, Omaha, NE, USA.
Published: June 2020
Introduction: Alpha 7 nicotinic acetylcholine receptor (α7 nAChR) partial agonists, agonists, and positive allosteric modulators (PAMs) have been in development for over a decade. The initial candidates were in clinical trials for a wide variety of diseases including schizophrenia, but there has yet to be a successful compound to make it to the market for any disorder. Although difficult to assess the cause of all the clinical failures, the lack of efficacy played a major role. The development of more selective compounds, may bring a successful compound to long-suffering schizophrenia patients.
Areas Covered: This article examines investigational agonists and positive allosteric modulators of the α7 nicotinic receptor in preclinical studies as well as clinical trials. Our search included the use of SciFinder, Google, and clinicaltrials.gov with search dates of 2015 to the present.
Expert Opinion: Researchers must rethink their approach should look more closely at the selectivity of new compounds and how to tackle the translational gap. Perhaps new positive allosteric modulators that can help minimize receptor desensitization and selectivity profiles can be a path forward for α7 nAChRs in schizophrenia.
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http://dx.doi.org/10.1080/13543784.2020.1764938 | DOI Listing |
BJC Rep
January 2025
Université Paris-Saclay, CEA, INRAE, Médicaments et Technologies pour la Santé (MTS), SPI, Laboratoire d'Etude de l'Unité Neurovasculaire et Innovation Thérapeutique (LENIT), Gif-sur-Yvette, France.
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Methods: We previously reported the rendomab B49 antibody (RB49) exhibiting a preferential affinity for the activated conformation of human endothelin B receptor (ET), not displaced by high endothelin levels, and without any pharmacological properties that could inhibit the division of melanoma cells.
Br J Pharmacol
January 2025
Department of Pharmacology, University of Oxford, Oxford, UK.
Background And Purpose: TMEM16A chloride channels constitute a depolarising mechanism in arterial smooth muscle cells (SMCs) and contractile cerebral pericytes. TMEM16A pharmacology is incompletely defined. We elucidated the mode of action and selectivity of a recently identified positive allosteric modulator of TMEM16A (PAM_16A) and of a range of TMEM16A inhibitors.
View Article and Find Full Text PDFTrends Pharmacol Sci
January 2025
Department of Anesthesiology and Washington University Pain Center, Washington University School of Medicine, St Louis, MO, USA; Center for Clinical Pharmacology, Washington University School of Medicine, St Louis, MO, USA. Electronic address:
Activation of the μ opioid receptor (MOR) can give analgesia, but also has dangerous side effects. Drugs that target MOR through an allosteric site, meaning they bind outside of the usual pocket, present a novel mode of receptor activation with different pharmacology relative to orthosteric drugs. Recent structural studies give valuable new information on how allosteric modulators interact with MOR.
View Article and Find Full Text PDFTransl Psychiatry
January 2025
Research Center Juelich, Institute of Neuroscience and Medicine 10, Research Center Juelich, Juelich, Germany.
Genetic variation in the α5 nicotinic acetylcholine receptor (nAChR) subunit of mice results in behavioral deficits linked to the prefrontal cortex (PFC). rs16969968 is the primary Single Nucleotide Polymorphism (SNP) in CHRNA5 strongly associated with nicotine dependence and schizophrenia in humans. We performed single cell-electrophysiology combined with morphological reconstructions on layer 6 (L6) excitatory neurons in the medial PFC (mPFC) of wild type (WT) rats, rats carrying the human coding polymorphism rs16969968 in Chrna5 and α5 knockout (KO) rats.
View Article and Find Full Text PDFJ Nat Prod
January 2025
Charlotte's Web, 700 Tech Court, Louisville, Colorado 80027, United States.
Cannabicyclol ((±)-CBL), a minor phytocannabinoid, is largely unexplored, with its biological activity previously undocumented. We studied its conversion from cannabichromene (CBC) using various acidic catalysts. Montmorillonite (K30) in chloroform at room temperature had the highest yield (60%) with minimal byproducts.
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