Muscarinic M1 Receptor Agonists and the Potential for Treating Alzheimer's Disease

        Neurodegenerative diseases are an area of medicine that continuously receive great attention and funding year after year. Despite the existence of many of these diseases, when one hears the term “neurodegenerative disease” most people immediately think of Alzheimer’s disease, which since its discovery, has represented one of the most urgent healthcare crises that exists in modern medicine, projecting to affect a whopping 75 million individuals by 2030 (Brown et al., 2021). Most of us know someone affected by this disease, and me personally, I lost my grandmother to it in 2018. For me, the battle against Alzheimer’s disease is one that is personal. Over the years, many treatments have faded in and out of the prospective spotlight. A glimpse of success here and there brings new hope to those with previously diagnosed loved ones, but we’re still further away from a cure than we think. 

          The beauty of science and medicine is that great researchers and scientists within the field never stop the search. An area of potential hope in the treatment of Alzheimer’s disease has been within the manipulation of the acetylcholine mediated muscarinic receptors, specifically M1, which plays a key role in cognitive function and behavior. A sort of arms race between pharmaceutical companies has occurred throughout the years, but adverse side effects have left drug developers back in the war rooms. The muscarinic receptors include a class of five receptors, M1-M5. Binding sites between the M1, M2 and M3 receptors share many biochemical similarities, and so the main question has now become, how can we specify M1 agonist binding, which could be crucial in treating Alzheimer’s disease, while reducing the side effects produced by unintended M2 and M3 agonist binding (Brown et al., 2021). And so, a drug currently in clinical trials termed HTL9936, designed to combat memory loss in patients with Alzheimer’s disease, was developed to accomplish just that. 

 

            So far, HTL9936 has shown great preclinical results in rats and nonhuman primates. In healthy human adults and elderly human subjects, activation of HTL9936 mediated receptors in cognitive related areas of the hippocampus was present. However, no improved spatial activity in the hippocampus of a small number of healthy elderly subjects was observed (Brown et al., 2021). The delivery of HTL9936 to the brain, as shown by plasma CNS drug levels in the CSF, and the subsequent activation of the hippocampus receptors, combined with the lack of M2 and M3 mediated side effects, shows great promise for continued research and an expansion of human clinical trials (Brown et al., 2021). Furthermore, this highlighted activity suggests that HTL9936, combined with the current standard for treatment, an acetylcholinesterase inhibitor donepezil, could prove to be an excellent tag team for future treatments (Brown et al., 2021). For now, research surrounding this drug should focus on human trials with greater amounts of human subjects, and eventually, the efficacy of the drug in patients with Alzheimer’s disease. 

 

References:

Brown AJH, Bradley SJ, Marshall FH, Brown GA, Bennett KA, Brown J, Cansfield JE, Cross DM, de Graaf C, Hudson BD, Dwomoh L, Dias JM, Errey JC, Hurrell E, Liptrot J, Mattedi G, Molloy C, Nathan PJ, Okrasa K, Osborne G, Patel JC, Pickworth M, Robertson N, Shahabi S, Bundgaard C, Phillips K, Broad LM, Goonawardena AV, Morairty SR, Browning M, Perini F, Dawson GR, Deakin JFW, Smith RT, Sexton PM, Warneck J, Vinson M, Tasker T, Tehan BG, Teobald B, Christopoulos A, Langmead CJ, Jazayeri A, Cooke RM, Rucktooa P, Congreve MS, Weir M, Tobin AB. From structure to clinic: Design of a muscarinic M1 receptor agonist with potential to treatment of Alzheimer's disease. Cell. 2021 Nov 24;184(24):5886-5901.e22. doi: 10.1016/j.cell.2021.11.001. PMID: 34822784.