Enantiomeric N-methyl-4-piperidyl benzilates as muscarinic receptor ligands: Radioligand binding studies and docking studies to models of the three muscarinic receptors M1, M2 and M3.
Benzilic ester derivatives with a basic moiety like N-methyl-4-piperidyl benzilates are potential drugs for the treatment of urinary incontinence, duodenal and gastric ulcers and Parkinson's disease. The effect of structural variations of chiral N-methyl-4-piperidyl benzilates was investigated using radioligand binding studies on muscarinic receptors (M1-M3). The results of the binding studies demonstrate that the absolute configuration and the aromatic substituent of benzilates have an influence on muscarinic affinity and selectivity. In this regard, (S)-configuration of benzilates and hydrophilic aromatic substituents seems to enhance muscarinic affinity. A model of the receptor ligand complex for N-methyl-4-piperidyl benzilates was obtained by molecular modelling. Both the affinity of enantiomeric benzilic esters and the subtype selectivity for muscarinic receptors are comprehensively explained by this model.
Selent
Jana
J
Department of Chemistry, Humboldt-University of Berlin, Brook-Taylor-Str. 2, D-12489 Berlin, Germany.
Brandt
Wolfgang
W
Pamperin
Dirk
D
Göber
Berthold
B
D000818:Animals; D001561:Benzilates / Q000737:chemistry* / Q000378:metabolism; D001665:Binding Sites; D002460:Cell Line; D003198:Computer Simulation; D008024:Ligands; D008956:Models, Chemical; D008958:Models, Molecular; D018721:Muscarinic Agonists / Q000737:chemistry* / Q000378:metabolism; D010880:Piperidines / Q000737:chemistry* / Q000378:metabolism; D011869:Radioligand Assay; D043643:Receptor, Muscarinic M1 / Q000737:chemistry; D043585:Receptor, Muscarinic M2 / Q000737:chemistry; D043587:Receptor, Muscarinic M3 / Q000737:chemistry; D011976:Receptors, Muscarinic / Q000737:chemistry*; D013237:Stereoisomerism
D001561:Benzilates; D008024:Ligands; D018721:Muscarinic Agonists; D010880:Piperidines; D043643:Receptor, Muscarinic M1; D043585:Receptor, Muscarinic M2; D043587:Receptor, Muscarinic M3; D011976:Receptors, Muscarinic