Synthesis of novel and functionally selective non‐competitive muscarinic antagonists as chemical probes

• Published in: Chemical biology & drug design Vol. 91; no. 1; pp. 93 - 104
• Main Authors: Boulos, John F., Jakubik, Jan, Boulos, John M., Randakova, Alena, Momirov, Jelena
• Format: Journal Article
• Language: English
• Published: HOBOKEN Wiley 01.01.2018
• Subjects: Acetylcholinesterase - metabolism; Allosteric Regulation; Animals; Binding Sites; Biochemistry & Molecular Biology; Chemistry, Medicinal; CHO Cells; Cricetinae; Cricetulus; Drug Design; G‐protein‐coupled receptor; Humans; Life Sciences & Biomedicine; Ligands; muscarinic acetylcholine receptor; Muscarinic Antagonists - chemical synthesis; Muscarinic Antagonists - chemistry; Muscarinic Antagonists - metabolism; N-Methylscopolamine - chemical synthesis; N-Methylscopolamine - chemistry; N-Methylscopolamine - metabolism; N‐methylscopolamine; Parkinson's disease; Pharmacology & Pharmacy; Pilot Projects; positive allosteric modulator; Protein Isoforms - chemistry; Protein Isoforms - genetics; Protein Isoforms - metabolism; Pyridines - chemistry; Receptors, Muscarinic - chemistry; Receptors, Muscarinic - genetics; Receptors, Muscarinic - metabolism; Science & Technology; ACETYLCHOLINE-RECEPTOR SUBTYPE; M-1; ACTIVATION; Parkinson's disease; BITOPIC LIGANDS; G-protein-coupled receptor; muscarinic acetylcholine receptor; N-methylscopolamine; XANOMELINE; AGONISTS; BINDING; positive allosteric modulator
• ISSN: 1747-0277; 1747-0285
• DOI: 10.1111/cbdd.13059

Muscarinic receptors are known to play important biological roles and are drug targets for several human diseases. In a pilot study, novel muscarinic antagonists were synthesized and used as chemical probes to obtain additional information of the muscarinic pharmacophore. The design of these ligands made use of current orthosteric and allosteric models of drug–receptor interactions together with chemical motifs known to achieve muscarinic receptor selectivity. This approach has led to the discovery of several non‐competitive muscarinic ligands that strongly bind at a secondary receptor site. These compounds were found to be non‐competitive antagonists that completely abolished carbachol activation in functional assays. Several of these compounds antagonized functional response to carbachol with great potency at M1 and M4 than at the rest of receptor subtypes. Synthesis of various functionally selective muscarinic antagonists that bind to all five receptor subtypes with similar affinity. Complete inhibition of the orthosteric antagonist [3H]NMS suggests steric interaction between tested compounds and [3H]NMS, while antagonism of carbachol‐induced functional response suggests non‐competitive interaction as potency of functional antagonism pKB is greater than affinity of the compounds pKI.