Discovery of Novel N-Substituted Oxindoles as Selective M₁ and M₄ Muscarinic Acetylcholine Receptors Partial Agonists

Abstract

Activation of the M1 and M4 muscarinic acetylcholine receptors is thought to play an important role in improving the symptoms of schizophrenia. However, discovery of selective agonists for these receptors has been a challenge, considering the high sequence homology and conservation of the orthosteric acetylcholine binding site among muscarinic acetylcholine receptor subtypes. We report in this study the discovery of novel N-substituted oxindoles as potent muscarinic acetylcholine receptor partial agonists selective for M1 and M4 over M2, M3, and M5. Among these oxindoles, compound 1 showed high selectivity for the M1 and M4 receptors with remarkable penetration into the central nervous system. Compound 1 reversed methamphetamine- and apomorphine-induced psychosis-like behaviors with low potency to extrapyramidical and peripheral side effects.

A Novel Phosphodiesterase 1 Inhibitor DSR-141562 Exhibits Efficacies in Animal Models for Positive, Negative, and Cognitive Symptoms Associated with Schizophrenia

“…Locomotor Activity Measurement in Rats. The locomotor activities were measured in male Sprague-Dawley rats as previously described with some modifications (Sumiyoshi et al, 2013). To evaluate the effects of DSR-141562 on spontaneous locomotor activities, rats were orally administered DSR-141562 (3, 10, and 30 mg/kg) or vehicle (0.5% methylcellulose) and returned to their home cages.…”

Enantioselective Hydrogenation of Racemic α-Arylamino Lactones to Chiral Amino Diols with Site-Specifically Modified Chiral Spiro Iridium Catalysts

“…SNX-0723 ( 2 ) is a brain-permeable, orally active selective inhibitor of Hsp 90 that prevents α-synuclein oligomerization (EC50 = 48 nM) . Molecule 3 is a structurally novel selective partial agonist of both the M1 and the M4 subtypes of the muscarinic acetylcholine receptor, and molecule 4 is a potent Rho kinase inhibitor. Because of the significance of chiral N -aryl-2-aminobutane-1,4-diols, the development of new, efficient, reliable methods for their stereoselective synthesis has attracted considerable research attention .…”

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

“…Although little attention has been given to further advancing orthosteric M 4 agonists, the drug development division of Sumitomo Dainippon Pharma in Japan published recent progress in developing dual M 1 /M 4 agonists (akin to Xanomeline) via the identification of scaffolds through HTS that were then coupled with known pharmacophores of M 4 PAMs and hybridized to discover lead compounds. Through their rather extensive SAR efforts, novel, highly selective M 1 /M 4 agonists based on N-substituted oxindole (blue, 7, Figure 5 ) [ 178 ], dihydroquinazolinone (green, 8, Figure 5 ) [ 179 ], and 7-azaindoline (red, 9, Figure 5 ) [ 180 ] were developed and evaluated in vitro. Compound 7 partially activated M 1 (EC 50 = 12 nM) and M 4 (EC 50 = 29 nM) while showing negligible off-target binding and potent CNS penetration.…”