• Leo Rex

Agonists of the Muscarinic Receptors (10)

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To read the previous article in this series, click here.

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By far the most well-known cognitive enhancing agonist of the mAChRs is arecoline, derived of the areca nut[1]. In Asian cultures, the areca nut is chewed with the betel leaf (known in the subcontinent as paan) for a stimulating effect, though the ancient practice has been shown to be carcinogenic[2]. Interestingly, there is evidence of paan chewing from the Philippines that predates the end of the Neolithic revolution[3].

Of the synthetic agonists of the mAChRs, the most notable are xanomeline, 11- (19-(2-methylbenzyl)-1,49-bipiperidin-4-yl)-1H-benzo[d]imidazol2(3H)-1 (called TBPB), benzylquinolone carboxylic acid (called BQCA), 77-LH-28-1, VU0357017, and VU0364572, although the racetam nebracetam also agonizes the M1 receptor selectively[4]. Xanomeline is well-known, whereas the other compounds in this list are mostly known to researchers and chemists specialized in the subject of cognitive decline. Nonetheless, the determined reader will find the compounds of import to cognitive enhancement.

Xanomeline is the least selective of the list. It agonizes both the M1 and M4 receptors, and it has the greatest antidopaminergic effect of the lot[5][6]. In placebo-controlled trials, xanomeline has been shown to improve cognition and behavior among Alzheimer’s patients[7], though it causes the gastrointestinal distress characteristic of less selective cholinergic drugs. On the other hand, TBPB is a selective partial agonist of M1 receptors that is the only compound on this list that also antagonizes M2-M5 receptors and antagonizes dopamine 2 receptors[8].

BQCA also has unusual characteristics. It is a positive allosteric modulator of the M1 receptor with no effect on the M2-M5 receptors[9]. Instead of directly agonizing the M1 receptor, it increases the action of orthosteric agonists like acetylcholine by over 2x[10]. The careful reader will recall that galantamine, the acetylcholinesterase inhibitor, had a similar secondary effect. Interestingly, BQCA has been shown in rodent studies to decrease amphetamine’s neurological effects[11], implying that it likely somehow antagonizes dopaminergic neurons, despite not directly agonizing the cholinergic receptors. While human trials have yet to begin, BQCA has been shown to improve learning and episodic memory in animal studies. Unfortunately, even the rodents experienced severe diarrhea[12], likely because the molecule crosses the blood-brain barrier poorly[13].

77-LH-28-1[14] selectively agonizes the M1 receptor with 100x greater affinity than the other muscarinic receptors. It also has the distinct quality of agonizing both the dopamine D2 receptors and the serotonin 5-HT2B receptors, which should yield an antidepressant effect.

VU0357017 is a weak partial allosteric agonist of M1 receptors that is selective over other muscarinic and biogenic amine receptors, though it exhibits a weak antagonism of D2 receptors. It has been shown to be liver-protective[15], in line with discoveries about the M1 receptor’s role in liver injury. Note that it is likely that the other agonists of the M1 receptor are also protective for the liver, though this aspect of their biochemistry has yet to be studied. Interestingly, Vanderbilt University (the producers of VU0357017, hence, VU) succeeded in removing its effect on D2 receptors by replacing its ethyl linker with a three-amino piperidine, resulting in VU0364572[16]. It is tempting to speculate that VU0364572 may provide the cognitive enhancing and liver protective effects of the other molecules on this list without interfering with the dopaminergic system.

To continue to the next blog post in this series, click here.

To return to an overview of the blog series on the cholinergic system, click here.

[1] Sullivan, R. J., Andres D Ch MS, PG Dip MH, S., Otto, C., Miles, W., & Kydd, R. (2007). The effects of an indigenous muscarinic drug, Betel nut (Areca catechu), on the symptoms of schizophrenia: a longitudinal study in Palau, Micronesia. American Journal of Psychiatry, 164(4), 670-673. [2] Nair, U., Bartsch, H., & Nair, J. (2004). Alert for an epidemic of oral cancer due to use of the betel quid substitutes gutkha and pan masala: a review of agents and causative mechanisms. Mutagenesis, 19(4), 251-262. [3] Zumbroich, T. J. (2008). The origin and diffusion of betel chewing: a synthesis of evidence from South Asia, Southeast Asia and beyond. E-Journal of Indian Medicine, 1(3), 87. [4] Kitamura, Y., Kaneda, T., & Nomura, Y. (1991). Effects of nebracetam (WEB 1881 FU), a novel nootropic, as a M1-muscarinic agonist. The Japanese Journal of Pharmacology, 55(1), 177-180. [5] Thomsen, M., Lindsley, C. W., Conn, P. J., Wessell, J. E., Fulton, B. S., Wess, J., & Caine, S. B. (2012). Contribution of both M 1 and M 4 receptors to muscarinic agonist-mediated attenuation of the cocaine discriminative stimulus in mice. Psychopharmacology, 220(4), 673-685. [6] Mirza, N. R., Peters, D., & Sparks, R. G. (2003). Xanomeline and the antipsychotic potential of muscarinic receptor subtype selective agonists. CNS drug reviews, 9(2), 159-186. [7] Bodick, N. C., Offen, W. W., Levey, A. I., Cutler, N. R., Gauthier, S. G., Satlin, A., ... & Hurley, D. J. (1997). Effects of xanomeline, a selective muscarinic receptor agonist, on cognitive function and behavioral symptoms in Alzheimer disease. Archives of neurology, 54(4), 465-473. [8] Sheffler, D. J., Sevel, C., Le, U., Lovell, K. M., Tarr, J. C., Carrington, S. J., ... & Hopkins, C. R. (2013). Further exploration of M1 allosteric agonists: Subtle structural changes abolish M1 allosteric agonism and result in pan-mAChR orthosteric antagonism. Bioorganic & medicinal chemistry letters, 23(1), 223-227. [9] Ellis, J., & Elmslie, G. (2016). Benzyl quinolone carboxylic acid (BQCA) elicits positive allosteric modulation at M2-M5 muscarinic receptors with specific mutations. The FASEB Journal, 30(1_supplement), lb519-lb519. [10] Chambon, C., Jatzke, C., Wegener, N., Gravius, A., & Danysz, W. (2012). Using cholinergic M1 receptor positive allosteric modulators to improve memory via enhancement of brain cholinergic communication. European journal of pharmacology, 697(1-3), 73-80. [11] Ma L, Seager MA, Wittmann M, Jacobson M, Bickel D, Burno M, Jones K, Graufelds VK, Xu G, Pearson M, McCampbell A, Gaspar R, Shughrue P, Danziger A, Regan C, Flick R, Pascarella D, Garson S, Doran S, Kreatsoulas C, Veng L, Lindsley CW, Shipe W, Kuduk S, Sur C, Kinney G, Seabrook GR, Ray WJ. Selective activation of the M1 muscarinic acetylcholine receptor achieved by allosteric potentiation. [12] Thomsen, M., Lindsley, C. W., Conn, P. J., Wessell, J. E., Fulton, B. S., Wess, J., & Caine, S. B. (2012). Contribution of both M 1 and M 4 receptors to muscarinic agonist-mediated attenuation of the cocaine discriminative stimulus in mice. Psychopharmacology, 220(4), 673-685. [13] Shirey, J. K., Brady, A. E., Jones, P. J., Davis, A. A., Bridges, T. M., Kennedy, J. P., ... & Christian, E. P. (2009). A selective allosteric potentiator of the M1 muscarinic acetylcholine receptor increases activity of medial prefrontal cortical neurons and restores impairments in reversal learning. Journal of Neuroscience, 29(45), 14271-14286. [14] Langmead, C. J., Austin, N. E., Branch, C. L., Brown, J. T., Buchanan, K. A., Davies, C. H., ... & Jones, G. A. (2008). Characterization of a CNS penetrant, selective M1 muscarinic receptor agonist, 77‐LH‐28‐1. British journal of pharmacology, 154(5), 1104-1115. [15] Jadeja, R. N., Urrunaga, N. H., Ahmad, D., & Khurana, S. (2016). Data regarding M1 muscarinic receptor-mediated modulation of hepatic catalase activity in response to oxidative stress. Data in brief, 6, 405-409. [16] Melancon, B. J., Tarr, J. C., Panarese, J. D., Wood, M. R., & Lindsley, C. W. (2013). Allosteric modulation of the M1 muscarinic acetylcholine receptor: improving cognition and a potential treatment for schizophrenia and Alzheimer's disease. Drug discovery today, 18(23-24), 1185-1199.




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