Discovery of Selective M4 Muscarinic Acetylcholine Receptor Agonists with Novel Carbamate Isosteres

Abstract

It has been hypothesized that selective muscarinic acetylcholine receptor (mAChR) M4 subtype activation could provide therapeutic benefits to a number of neurological disorders while minimizing unwanted cholinergic side effects observed due to nonselective mAChR activation. Given the high sequence and structural homology of the orthosteric binding sites among mAChRs, achieving M4 subtype-selective activation has been challenging. Herein, we describe the discovery of a series of M4 subtype-selective agonists bearing novel carbamate isosteres. Comparison of the isosteres' electrostatic potential isosurface sheds light on key structural features for M4 subtype-selective activation. The identified key features were further illustrated in a proposed receptor−agonist interaction mode.

The structural study of mutation-induced inactivation of human muscarinic receptor M4

“…The N449 7.49 R substitution allowed an unknown hydrophobic ligand to be trapped in a hydrophobic pocket of the orthosteric site, which further stabilized the inactive state. This rotation of Y439 7.39 also occurs in the docking results for some other M4-selective agonists, in which Y439 7.39 adopted an 'open' conformation in all selected templates, including the agonist iperoxo (Yang et al, 2019), which differs from what was observed in the reported X-ray structure of the activated form of M2 (Kruse et al, 2013). The conformations of the orthosteric and allosteric sites are coupled such that the presence of a ligand in one site affects the shape of the other (Burger et al, 2018).…”

Drug Design Targeting the Muscarinic Receptors and the Implications in Central Nervous System Disorders

“…These efforts quickly encountered the challenge of retaining M 4 activity, leading to a shift in focus to exploring heteroaromatics. Pyrazine (orange, Figure 5 ) and 1,2,3-thiadiazoles (similar to Xanomeline) were identified as effective ethyl carbamate replacements, resulting in lead compound 10 that demonstrated ~29-fold selectivity for M 4 [EC50 = 0.296 μM] over M 2 [ > 8.83 μM] [ 181 ]. Due to a high conservation in the orthosteric site, recent efforts in the Pfizer program have shifted focus again, although to designing functionally selective allosteric modulators targeting the M 1 and M 4 receptors this time (see below).…”

“…Achieving selectivity at the orthosteric site proved to be a daunting task, as evidenced by unwanted cholinergic AEs in early clinical trials with Xanomeline, hence Lilly’s efforts focused on developing M 4 PAMs. Lead compound LY2033298 displayed robust cooperativity to ACh and had suitable physicochemical properties for in vivo dosing [ 181 ]. It potentiated the behavioral effects of the nonselective mAChR agonist oxotremorine (OXO-M) in reversing apomorphine-induced disruption of pre-pulse inhibition and conditioned avoidance responding [ 182 , 183 ].…”

Novel benzenesulfonamide‐bearing pyrazoles and 1,2,4‐thiadiazoles as selective carbonic anhydrase inhibitors

“…However, our efforts to synthesize thioureido‐linked isoxazoles 9 led to the formation of amino‐1,2,4‐thiadiazoles 10 as the final product in place of the anticipated isoxazoles 9 . Further, a literature survey revealed that the 1,2,4‐thiadiazole moiety has significant medicinal applications [ 42–46 ] and can be investigated as a potent pharmacological candidate. Therefore, to investigate the CA inhibition profile of amino‐1,2,4‐thiadiazoles 10 and to compare the results with thioureido‐linked pyrazoles 8 , a total of 20 derivatives were synthesized from both series in this study.…”