Both historical clinical and recent preclinical data suggest that the M muscarinic acetylcholine receptor is an exciting target for the treatment of Alzheimer's disease and the cognitive and negative symptom clusters in schizophrenia; however, early drug discovery efforts targeting the orthosteric binding site have failed to afford selective M activation. Efforts then shifted to focus on selective activation of M via either allosteric agonists or positive allosteric modulators (PAMs). While M PAMs have robust efficacy in rodent models, some chemotypes can induce cholinergic adverse effects (AEs) that could limit their clinical utility. Here, we report studies aimed at understanding the subtle structural and pharmacological nuances that differentiate efficacy from adverse effect liability within an indole-based series of M ago-PAMs. Our data demonstrate that closely related M PAMs can display striking differences in their in vivo activities, especially their propensities to induce adverse effects. We report the discovery of a novel PAM in this series that is devoid of observable adverse effect liability. Interestingly, the molecular pharmacology profile of this novel PAM is similar to that of a representative M PAM that induces severe AEs. For instance, both compounds are potent ago-PAMs that demonstrate significant interaction with the orthosteric site (either bitopic or negative cooperativity). However, there are subtle differences in efficacies of the compounds at potentiating M responses, agonist potencies, and abilities to induce receptor internalization. While these differences may contribute to the differential in vivo profiles of these compounds, the in vitro differences are relatively subtle and highlight the complexities of allosteric modulators and the need to focus on in vivo phenotypic screening to identify safe and effective M PAMs.
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http://dx.doi.org/10.1021/acschemneuro.6b00429 | DOI Listing |
Proc Natl Acad Sci U S A
January 2025
Department of Psychological and Brain Sciences, Indiana University, Bloomington, IN 47405.
Dysregulation of GABAergic inhibition is associated with pathological pain. Consequently, enhancement of GABAergic transmission represents a potential analgesic strategy. However, therapeutic potential of current GABA agonists and modulators is limited by unwanted side effects.
View Article and Find Full Text PDFEur J Epidemiol
January 2025
Department of Psychiatry, Virginia Institute for Psychiatric and Behavioral Genetics, Virginia Commonwealth University, 800 E. Leigh St., Suite 100, Richmond, VA, 23298, USA.
Cigarette smoking is associated with numerous differentially-methylated genomic loci in multiple human tissues. These associations are often assumed to reflect the causal effects of smoking on DNA methylation (DNAm), which may underpin some of the adverse health sequelae of smoking. However, prior causal analyses with Mendelian Randomisation (MR) have found limited support for such effects.
View Article and Find Full Text PDFAm J Sports Med
January 2025
Department of Orthopaedic Surgery, Hospital for Special Surgery, New York, New York, USA.
Background: Failure of primary cartilage restoration procedures of the knee that proceed to necessitating revision cartilage procedures represent a challenging clinical scenario with variable outcomes reported in previous literature.
Purpose: To perform a systematic review and meta-analysis of clinical outcomes and adverse events after revision cartilage restoration procedures of the knee for failed primary cartilage procedures.
Study Design: Systematic review and meta-analysis; Level of evidence, 4.
Am J Sports Med
January 2025
Case Western Reserve University School of Medicine, Cleveland, Ohio, USA.
Background: Selective androgen receptor modulators (SARMs) are small-molecule compounds that exert agonist and antagonist effects on androgen receptors in a tissue-specific fashion. Because of their performance-enhancing implications, SARMs are increasingly abused by athletes. To date, SARMs have no Food and Drug Administration approved use, and recent case reports associate the use of SARMs with deleterious effects such as drug-induced liver injury, myocarditis, and tendon rupture.
View Article and Find Full Text PDFAm J Sports Med
January 2025
Department of Sports Medicine, Peking University Third Hospital; Institute of Sports Medicine of Peking University; Beijing Key Laboratory of Sports Injuries, Beijing, China.
Background: There is a lack of evidence and continuous debate on whether femoral tunnel displacement substantially influences the clinical efficacy of medial patellofemoral ligament reconstruction (MPFL-R) in addressing recurrent patellar dislocation.
Purpose: To investigate possible associations between inaccurate femoral tunnel placement during MPFL-R and clinical outcomes, with a specific focus on proximal tunnel malpositioning.
Study Design: Cohort study; Level of evidence, 3.
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