Proof of Concept Study for Designed Multiple Ligands Targeting the Dopamine D2, Serotonin 5‑HT2A, and Muscarinic M1 Acetylcholine Receptors

• Published in: Journal of medicinal chemistry Vol. 58; no. 3; pp. 1550 - 1555
• Main Authors: Szabo, Monika, Lim, Herman D, Klein Herenbrink, Carmen, Christopoulos, Arthur, Lane, J. Robert, Capuano, Ben
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 12-02-2015
• Subjects: Benzoxazines - chemical synthesis; Benzoxazines - chemistry; Benzoxazines - pharmacology; Dopamine D2 Receptor Antagonists - chemical synthesis; Dopamine D2 Receptor Antagonists - chemistry; Dopamine D2 Receptor Antagonists - pharmacology; Dose-Response Relationship, Drug; Drug Design; Ligands; Molecular Structure; Receptor, Muscarinic M1 - antagonists & inhibitors; Receptor, Muscarinic M1 - metabolism; Receptor, Serotonin, 5-HT2A - metabolism; Receptors, Dopamine D2 - metabolism; Serotonin 5-HT2 Receptor Antagonists - chemical synthesis; Serotonin 5-HT2 Receptor Antagonists - chemistry; Serotonin 5-HT2 Receptor Antagonists - pharmacology; Structure-Activity Relationship
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm5013243

Herein we describe the hybridization of a benzoxazinone M1 scaffold with D2 privileged structures derived from putative and clinically relevant antipsychotics to develop designed multiple ligands. The M1 mAChR is an attractive target for the cognitive deficits in key CNS disorders. Moreover, activity at D2 and 5-HT2A receptors has proven useful for antipsychotic efficacy. We identified 9 which retained functional activity at the target M1 mAChR and D2R and demonstrated high affinity for the 5-HT2AR.