title: Synthesis, muscarinic blocking activity and molecular modeling studies of 4-DAMP-related compounds.
abstract: A number of compounds structurally related to 4-DAMP (1) were synthesized and a single crystal X-ray structural study on a representative member of this series was carried out. All the compounds were tested for the antagonist activity in isolated guinea pig atria (M2 muscarinic receptors) and ileum (M3 muscarinic receptors). Affinity values (pA2) for the muscarinic receptor subtypes ranged from 5.39 to 9.71 (M2) and from 5.68 to 9.92 (M3), depending on different structural features of the compounds. A molecular modeling study was performed, with the aim of rationalizing the affinity data for both M2 and M3 muscarinic receptor subtypes. The presence in the series of two highly active, structurally constrained derivatives allowed us to define two different pharmacophoric frames on which all the compounds could be fitted in a satisfactory manner.
authors.affiliation: Department of Pharmaceutical Sciences, University of Bologna, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Recanatini
authors.forename: V
authors.initials: V
authors.lastname: Tumiatti
authors.forename: R
authors.initials: R
authors.lastname: Budriesi
authors.forename: A
authors.initials: A
authors.lastname: Chiarini
authors.forename: P
authors.initials: P
authors.lastname: Sabatino
authors.forename: M L
authors.initials: ML
authors.lastname: Bolognesi
authors.forename: C
authors.initials: C
authors.lastname: Melchiorre
mesh_terms: D000818:Animals; D018360:Crystallography, X-Ray; D006168:Guinea Pigs; D007082:Ileum / Q000187:drug effects; D008958:Models, Molecular; D008968:Molecular Conformation; D015394:Molecular Structure; D018727:Muscarinic Antagonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D009206:Myocardium / Q000378:metabolism; D010880:Piperidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D011976:Receptors, Muscarinic / Q000378:metabolism
chemical_list: D018727:Muscarinic Antagonists; D010880:Piperidines; D011976:Receptors, Muscarinic; C042375:4-diphenylacetoxy-1,1-dimethylpiperidinium